Clinical Trials Register

Summary
EudraCT Number:	2015-005776-24
Sponsor's Protocol Code Number:	MRY-IIA-2015-01
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:	2016-03-01
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

Spain - AEMPS

A.2

EudraCT number

2015-005776-24

A.3

Full title of the trial

Intensive treatment of blood pressure in acute ischemic stroke. TICA 2 study.

Tratamiento intensivo de la presión arterial en el ictus isquémico agudo. Estudio TICA 2.

A.3.1

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

Control of blood pressure in stroke

Control de la presión arterial en el ictus

A.3.2

Name or abbreviated title of the trial where available

Estudio TICA 2

A.4.1

Sponsor's protocol code number

MRY-IIA-2015-01

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	Dr. Manuel Rodríguez Yáñez
B.1.3.4	Country	Spain
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	Instituto de Salud Carlos III
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Meditrial
B.5.2	Functional name of contact point	General Director
B.5.3	Address:
B.5.3.1	Street Address	Avda Nazaret 4 Bajo Drcha.
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28009
B.5.3.4	Country	Spain
B.5.4	Telephone number	34915745534
B.5.6	E-mail	info@meditrial.es

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	Trandate 5 mg/ml solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Kern Pharma, S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LABETALOL HYDROCHLORIDE
D.3.9.1	CAS number	32780-64-6
D.3.9.4	EV Substance Code	SUB02844MIG
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	Elgadil 5mg/ml solution for infusion and injection
D.2.1.1.2	Name of the Marketing Authorisation holder	TAKEDA FARMACÉUTICA ESPAÑA, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	URAPIDIL
D.3.9.1	CAS number	34661-75-1
D.3.9.4	EV Substance Code	SUB11384MIG
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: 3
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	NITROPRUSSIAT FIDES injectable
D.2.1.1.2	Name of the Marketing Authorisation holder	Rottapharm, S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SODIUM NITROPRUSSIDE
D.3.9.1	CAS number	13755-38-9
D.3.9.4	EV Substance Code	SUB12302MIG
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: 4
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	Urapidil Accord 5mg/ml solution for infusion and injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare, S.L.U.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	URAPIDIL
D.3.9.1	CAS number	34661-75-1
D.3.9.4	EV Substance Code	SUB11384MIG
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: 5
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	Trandate 5 mg/ml solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Kern Pharma, S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LABETALOL HYDROCHLORIDE
D.3.9.1	CAS number	32780-64-6
D.3.9.4	EV Substance Code	SUB02844MIG
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: 6
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	Elgadil 5mg/ml solution for infusion and injection
D.2.1.1.2	Name of the Marketing Authorisation holder	TAKEDA FARMACÉUTICA ESPAÑA, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	URAPIDIL
D.3.9.1	CAS number	34661-75-1
D.3.9.4	EV Substance Code	SUB11384MIG
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: 7
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	NITROPRUSSIAT FIDES injectable
D.2.1.1.2	Name of the Marketing Authorisation holder	Rottapharm, S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SODIUM NITROPRUSSIDE
D.3.9.1	CAS number	13755-38-9
D.3.9.4	EV Substance Code	SUB12302MIG
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: 8
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	Urapidil Accord 5mg/ml solution for infusion and injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare, S.L.U.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	URAPIDIL
D.3.9.1	CAS number	34661-75-1
D.3.9.4	EV Substance Code	SUB11384MIG
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

Ictus isquémico agudo

E.1.1.1

Medical condition in easily understood language

Ischemic stroke

Ictus

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10055221
E.1.2	Term	Ischemic stroke
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Demonstrate that maintaining systolic blood pressure between 140 and 160 mm Hg during the acute phase of ischemic stroke is more effective than management by Guidelines recommendation (try when systolic blood pressure 185 mm Hg exceeding).

Demostrar que el mantenimiento de una presión arterial sistólica entre 140 y 160 mm Hg durante la fase aguda del ictus isquémico es más eficaz que el manejo según las Guías de recomendación internacional (tratar cuando la presión arterial sistólica exceda de 185 mm Hg).

E.2.2

Secondary objectives of the trial

- Demonstrate that the maintenance over 72 hours of systolic blood pressure between 140 and 160 mm Hg during the acute phase of ischemic stroke, determines a smaller percentage of early neurological deterioration, relative to conventional treatment according to international guidelines.
- Demonstrate that the maintenance for 72 hours a systolic blood pressure between 140 and 160 mm Hg during the acute phase of ischemic stroke, reduces infarct volume (valued at neuroimaging at 24 hours) compared with conventional treatment according Guides international.
- Demonstrate that the maintenance over 72 hours of systolic blood pressure between 140 and 160 mm Hg during the acute phase of ischemic stroke reduces mortality at 90 days measured relative to conventional management according to international guidelines.
- Evaluate security between the two branches.

- Demostrar que el mantenimiento durante 72 horas de una presión arterial sistólica entre 140 y 160 mm Hg durante la fase aguda del ictus isquémico, condiciona un menor porcentaje de deterioro neurológico precoz, en relación con el tratamiento convencional según las Guías internacionales.
- Demostrar que el mantenimiento durante 72 horas de una presión arterial sistólica entre 140 y 160 mm Hg durante la fase aguda del ictus isquémico, disminuye el volumen del infarto (valorado en neuroimagen a las 24 horas) en relación con el tratamiento convencional según las Guías internacionales.
- Demostrar que el mantenimiento durante 72 horas de una presión arterial sistólica entre 140 y 160 mm Hg durante la fase aguda del ictus isquémico, disminuye la mortalidad medida a los 90 días en relación con el manejo convencional según las Guías internacionales.
- Evaluar la seguridad entre ambas ramas.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Men or women aged 18 and up to 85 years inclusive.
• Diagnosis clinical and neuroimaging (CT or MRI) of ischemic stroke.
• Ability to initiate antihypertensive treatment within 12 hours after the onset of symptoms (in the case of stroke, it is considered the start time as the time in which the patient has been asymptomatic last seen).
• Participating with systolic blood pressure greater than or equal to 140 mm Hg and less than or equal to 220 mmHg at the time of inclusion.
• Participant or able to understand the requirements of the study and sign the informed consent legal representative.

• Hombres o mujeres con 18 años cumplidos y hasta 85 años, inclusive.
• Diagnóstico clínico y por neuroimagen (TC o RM) de ictus isquémico.
• Posibilidad de iniciar el tratamiento antihipertensivo dentro de las 12 horas siguientes tras el inicio de los síntomas (en el caso de ictus, se considera la hora de inicio como la hora en la que el paciente ha sido visto asintomático por última vez).
• Participante con presión arterial sistólica mayor o igual de 140 mm Hg y menor o igual de 220 mm Hg en el momento de la inclusión.
• Participante o representante legal capaz de comprender los requisitos del estudio y firmar el consentimiento informado.

E.4

Principal exclusion criteria

• Uncontrollable hypertension (high SBP 220 mm Hg) or any condition that needs urgent antihypertensive treatment.
• Having had a stroke in the last 90 days in the same territory as current stroke.
• Having suffered a heart attack in the previous 90 days.
• Suspected aortic dissection, or hypertensive encephalopathy.
• Presence of intracerebral or subarachnoid hemorrhage in the basal neuroimaging (CT or MRI).
• It is probable realization has been made or intra-arterial recanalization techniques by the current stroke.
• Occlusion or critical carotid stenosis known.
• Be a candidate for carotid revascularization in the next three months.
• previous alterations that, according to the investigator, may interfere with the interpretation of neurological scales.
• Eat or low level of consciousness (defined as a score ≥ 2 in paragraph 1a of the NIHSS), dementia or mental impairment that judgment of the investigator makes the patient is unable to participate in the study.
• Seizures at any time from the onset of symptoms to the initial assessment.
• neurological or Comorbidities nonneurological that, according to the researcher, can carry, regardless of the current stroke, a deterioration in neurological status of the patient during the study period, or may hinder the evaluation of neurological status caused only by the stroke ( eg., metabolic encephalopathies, hemiplegic migraine, multiple sclerosis, tumor central, epilepsy, monocular blindness) nervous system.
• Be likely to undergo a procedure involving extracorporeal circulation during the study period.
• Any condition that, in the opinion of the investigator, would compromise the patient's ability to complete the study (eg. Comorbid conditions that may threaten the patient's life, such as neoplasms or terminal organ failure).
• Disability previous patient, determined by a score on the mRS> 1.
• Women of childbearing age with positive pregnancy test or lactating at the time of inclusion.
• Women of childbearing age (menopause less than 2 years or not surgically sterilized) not going to make effective and appropriate measures to prevent conception during the study period. Control measures include hormonal contraceptives, barrier methods such as diaphragm or intrauterine devices and / or condoms with spermicide.
• Current Unit substances of abuse such as alcohol, sympathomimetic amines, cannabis, cocaine, hallucinogens, opioids, fenciciclina, sedatives or hypnotics.
• Life expectancy is less than the expected duration of the clinical trial or any situation which, in the opinion of the investigator, may make dangerous participation in the clinical trial (eg. Drug, alcohol addiction, etc ...).
• Have received a drug or product under study or participate in a clinical trial within 30 days prior to the date of inclusion in the study.

• Hipertensión incontrolable (TAS mayor de 220 mm Hg) o cualquier condición que precise de un tratamiento antihipertensivo urgente.
• Haber sufrido un ictus en los 90 días previos en el mismo territorio que el ictus actual.
• Haber sufrido un infarto de miocardio en los 90 días previos.
• Sospecha de disección aórtica o encefalopatía hipertensiva.
• Presencia de hemorragia intracerebral o subaracnoidea en la neuroimagen basal (tomografía computarizada o resonancia magnética).
• Sea probable la realización o que se haya realizado técnicas de recanalización intraarterial por el ictus actual.
• Oclusión o estenosis carotidea crítica conocida.
• Ser candidato a revascularización carotidea en los próximos tres meses.
• Alteraciones previas que, a juicio del investigador, puedan interferir en la interpretación de las escalas neurológicas.
• Coma o bajo nivel de consciencia (definido como una puntuación ≥ 2 en el apartado 1.a de la NIHSS), demencia o discapacidad mental que a juicio del investigador haga que el paciente sea incapaz de participar en el estudio.
• Crisis convulsivas en cualquier momento desde el inicio de los síntomas hasta la evaluación inicial.
• Comorbilidades neurológicas o no neurológicas que, a juicio del investigador, puedan llevar, independientemente del ictus actual, a un deterioro en el estado neurológico del paciente durante el periodo del estudio, o puedan dificultar la evaluación del estado neurológico ocasionado sólo por el ictus (ej., encefalopatías metabólicas, migraña hemipléjica, esclerosis múltiple, tumor del sistema nervioso central, epilepsia, ceguera monocular).
• Sea probable someterse a un procedimiento que implique la circulación extracorpórea durante el período de estudio.
• Cualquier condición que, a juicio del investigador, pueda comprometer la capacidad del paciente de completar el estudio (ej. enfermedades concomitantes que puedan amenazar la vida del paciente, como neoplasias o insuficiencia terminal de un órgano).
• Incapacidad previa del paciente, determinada por una puntuación en la mRS > 1.
• Mujeres en edad fértil con test de embarazo positivo o en periodo de lactancia en el momento de la inclusión.
• Mujer en edad fértil (menopausia de menos de 2 años o no quirúrgicamente esterilizadas) que no vayan a realizar medidas eficaces y adecuadas para evitar la concepción durante el periodo del estudio. Las medidas de control incluyen anticonceptivos hormonales, métodos de barrera como diafragma o dispositivos intrauterinos y/o preservativos con espermicidas.
• Dependencia actual de sustancias de abuso como alcohol, aminas simpaticomiméticas, cannabis, cocaína, alucinógenos, opioides, fenciciclina, sedantes o hipnóticos.
• Expectativa de vida sea inferior a la duración prevista del ensayo clínico o cualquier situación que, a criterio del investigador, pueda hacer peligrosa la participación en el ensayo clínico (ej. consumo de drogas, adicción al alcohol, etc...).
• Haber recibido un fármaco o producto en estudio o participar en un ensayo clínico en los 30 días previos a la fecha de inclusión en el estudio.

E.5 End points

E.5.1

Primary end point(s)

Functional prognosis measured at 90 ± 15 days by modified Rankin scale.

Pronóstico funcional medido a los 90±15 días mediante la escala de Rankin modificada.

E.5.1.1

Timepoint(s) of evaluation of this end point

90 ± 15 days

90 ± 15 días

E.5.2

Secondary end point(s)

- early neurological deterioration (DNP): Increased 4 or more points on the NIHSS scale in any determination within 72 hours compared with baseline score.
- infarct volume: infarct volume in neuroimaging (CT or MRI) between 4th-7th day after stroke is determined. the volume in mL is calculated using the formula a x b x c x 0.5, where "a" and "b" are the largest diameter perpendicular in centimeters and "c" the number of cuts of 1 cm in display infarction.
- mortality: mortality shall be considered as any patient who dies from inclusion (signed informed consent) to the final study visit (90 ± 15 days)
- assessment of the safety of administering riboflavin in patients with clinical suspicion of stroke is performed by measuring adverse events throughout the study.

o Deterioro neurológico precoz (DNP): Incremento en 4 o más puntos en la escala NIHSS en cualquier determinación durante las primeras 72 horas comparado con la puntuación basal.
o Volumen del infarto: Se determinará el volumen del infarto en neuroimagen (TC o RM) realizada entre 4º-7º día tras el ictus. Se calculará el volumen en mL, usando la fórmula a x b x c x 0.5, donde “a” y “b” son los diámetros mayores en sentido perpendicular en centímetros y “c” el número de cortes de 1 cm en los que se vea el infarto.
o Mortalidad: Se considerará mortalidad como cualquier paciente que fallezca desde la inclusión (firma del consentimiento informado) hasta la visita final del estudio (90±15 días)
o La evaluación de la seguridad de la administración de riboflavina en pacientes con sospecha clínica de ictus se realizará mediante la medida de los acontecimientos adversos ocurridos a lo largo del estudio.

E.5.2.1

Timepoint(s) of evaluation of this end point

- Early neurological deterioration: within first72 hours.
- Volume of infarction: between 4th-7th day after the stroke.
- Mortality: from inclusion to the final study visit (90 ± 15 days)
- Security: all visits.

- Deterioro neurológico precoz: durante las primeras 72 horas.
- Volumen del infarto: entre 4º-7º día tras el ictus.
- Mortalidad: desde la inclusión hasta la visita final del estudio (90±15 días).
- Seguridad: en todas las visitas.

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)

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

blood pressure control according to international guidelines

Control de la presion arterial según guias internacionales

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

LPLV

Última visita del último paciente

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:

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

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.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)

It is not different from the expected normal treatment of that condition

No es diferente del tratamiento normal esperado para la enfermedad en estudio

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

2016-10-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-09-20

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