Clinical Trials Register

Summary
EudraCT Number:	2013-000657-50
Sponsor's Protocol Code Number:	PM1116197
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:	2014-04-25
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

2013-000657-50

A.3

Full title of the trial

A Clinical Outcomes Study to Compare the Incidence of Major Adverse Cardiovascular Events in Subjects Presenting with Acute Coronary Syndrome Treated with Losmapimod Compared to Placebo (PM1116197)

Short title: LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE (LATITUDE)-TIMI 60

Estudio de variables clínicas para comparar la incidencia de eventos adversos cardiovasculares importantes (MACE) en sujetos con síndrome coronario agudo tratados con losmapimod frente a placebo

Título corto: LosmApimod para Inhibir MAP cinasa p38 como diana TerapéUtica y moDificar los resultados después de padecer síndromE coronario agudo (LATITUDE)-TIMI 60

A.3.1

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

PM1116197 is a Clinical Study to Compare the Incidence of Major Adverse Cardiovascular Events in Subjects Presenting with Acute Coronary Syndrome Treated with Losmapimod Compared to Placebo

PM1116197 es un estudio clínico para comparar la incidencia de eventos adversos cardiovasculares en sujetos con síndrome coronario agudo tratados con losmapimod frente a placebo.

A.4.1

Sponsor's protocol code number

PM1116197

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1150-5007

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	GlaxoSmithKline, S.A.
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GlaxoSmithKline Research & Development Ltd
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline, S.A.
B.5.2	Functional name of contact point	Centro de Información
B.5.3	Address:
B.5.3.1	Street Address	C/Severo Ochoa, 2 (P.T.M.)
B.5.3.2	Town/ city	Tres Cantos (Madrid)
B.5.3.3	Post code	28760
B.5.3.4	Country	Spain
B.5.4	Telephone number	902202700
B.5.5	Fax number	918070479
B.5.6	E-mail	es-ci@gsk.com

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	No
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	Losmapimod
D.3.2	Product code	GW856553
D.3.4	Pharmaceutical form	Tablet
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	Losmapimod
D.3.9.1	CAS number	585543-15-3
D.3.9.2	Current sponsor code	GW856553
D.3.9.3	Other descriptive name	GW 856553X
D.3.9.4	EV Substance Code	SUB23045
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	7.5
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

hospitalized due to a heart attack, usually caused by a blockage in one or more of the arteries (blood vessels) in the heart

hospitalización debido a un infarto causado por el bloqueo en una o más arterias coronarias

E.1.1.1

Medical condition in easily understood language

hospitalized due to a heart attack, usually caused by a blockage in one or more of the arteries (blood vessels) in the heart

hospitalización debido a un infarto causado por el bloqueo en una o más arterias coronarias

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10003723
E.1.2	Term	Attack coronary
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	PT
E.1.2	Classification code	10051592
E.1.2	Term	Acute coronary syndrome
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10071111
E.1.2	Term	Non ST segment elevation acute coronary syndrome
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10041894
E.1.2	Term	ST segment elevation
E.1.2	System Organ Class	100000004848

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 is to evaluate the efficacy of oral losmapimod 7.5 mg BID compared to placebo when added to standard of care in subjects with ACS on the time to first occurrence of adjudicated MACE (defined as CV death, MI, or severe recurrent ischemia [SRI-UR]) through 12 weeks of therapy.

El objetivo principal consiste en evaluar la eficacia de 7,5 mg de losmapimod administrados por vía oral BID en comparación con placebo cuando se incorpora al tratamiento de referencia en sujetos con SCA en el momento en el que aparece por primera vez un MACE adjudicado (definido como muerte cardiovascular [CV], IM, o isquemia recurrente grave que requiere revascularización urgente de la arteria coronaria [IRG-UR]) a lo largo de las 12 semanas de tratamiento.

E.2.2

Secondary objectives of the trial

The principal secondary objective is to evaluate the efficacy of losmapimod on the time to first occurrence of adjudicated CV death or MI. Additional secondary objectives are included in the protocol page 21.

El principal objetivo secundario es evaluar la eficacia de losmapimod en el tiempo hasta la primera incidencia de IM o muerte CV adjudicada. Para objetivos secundarios adiciones vease la Sección 2.2. del Protocolo.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

1. Renal and Expanded Laboratory Substudy - The objective of the expanded laboratory analysis is to further characterize the effect of losmapimod on inflammatory and renal biomarkers
2. Pharmacokinetic Assessments for Subjects (n=3850) Enrolled in a PK Substudy - The objective of the pharmacokinetic analyses is to further develop the population PK model previously developed in Phase 2 in order to predict individual losmapimod exposures

1. Sub-estudio renal ? el objetivo de este subestudio es analizar los efectos de losmapimod en procesos inflamatorios y sobre biomarcadores renales.
2. Sub-estudio de Farmacocinética (n= 3850) el objetivo es analizar la farmacocinética de Losmapimod en determinados individuos para confirmar el modelo construido en el desarrollo de la fase 2 del producto.

E.3

Principal inclusion criteria

1.Signed written informed consent prior to beginning study-related procedures.
The subject must understand the aims, investigational procedures and possible consequences of the study
2.Male or female aged 35 years or older at randomization.
A female subject is eligible to participate if she is of non-child bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea or if of child-bearing potential is using a highly effective method for avoidance of pregnancy (refer to Appendix 1) for the duration of dosing and until 2 weeks post last-dose. The decision to include or exclude women of childbearing potential may be made at the discretion of the investigator and in accordance with local practice in relation to adequate contraception.
3.Hospitalization for NSTEMI or STEMI (Universal Definition Type 1 MI).
NSTEMI that is presumed spontaneous (Universal Definition Type 1) and is defined as ischemic chest discomfort (or equivalent) that occurs or persists at rest with at least 1 episode lasting ?10 minutes and is accompanied by a diagnostic elevation in cardiac troponin above the upper limit of normal (99th percentile decision-limit) according to the local laboratory without persistent ST segment elevation. If cardiac troponin is not available, then creatine-kinase MB isoenzyme (CK-MB) must be above the upper limit of normal. The biomarker should exhibit a rising and/or falling pattern when serial testing is available prior to randomization.
STEMI is defined as ischemic chest discomfort (or equivalent) that occurs or persists at rest with ST segment elevation of at least 0.1 mV in 2 or more contiguous leads or new (or presumed new) left bundle branch block (LBBB) and a presumed diagnosis of STEMI.
NOTE: Subjects with clinical or laboratory manifestations of ACS (e.g., ST-elevation or increase in cardiac enzymes) that are believed to be secondary to other apparent illness (e.g., sepsis, profound anemia, hypertensive emergency or decompensated heart failure, coronary embolism or dissection; Universal Type 2 MI) or known to be procedurally related (Type 4 - including stent thrombosis- or Type 5) are not considered to meet these criteria for NSTEMI or STEMI.
4.With the following timing of symptoms:
NSTEMI: Presence of ischemic symptoms (?5 minutes) at rest within 24 hours prior to randomization (may include qualifying episode).
STEMI: Onset of qualifying ischemic symptoms within 12 hours of randomization.
5.All subjects must also have at least one of the following additional predictors of cardiovascular risk:
a.Age ?60 years at randomization.
b.History of documented MI (known or presumed Type 1 MI) prior to qualifying ACS event.
c.History of CABG prior to qualifying ACS event.
d.NSTEMI with new ischemic ST-segment depression ?0.1 mV in ?2 contiguous leads.
e.Diabetes mellitus requiring pharmacotherapy.
f.Coexistent clinically diagnosed arterial disease in at least 1 peripheral arterial territory, defined as:
?History of non-cardioembolic (known or presumed), ischemic stroke (confirmed by medical records or history) or
?Current or history of peripheral arterial disease: current intermittent claudication with an ankle-brachial index ?0.85 or history of peripheral arterial stenting or surgery (including amputation due to vascular causes).

French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

1.Consentimiento informado por escrito firmado antes de iniciar los procedimientos relacionados con el estudio.
El sujeto debe comprender los objetivos, procedimientos de investigación y posibles consecuencias del estudio.
2.Hombre o mujer de 35 años de edad o más en el momento de la aleatorización.
Una paciente es elegible para participar si no se encuentra en edad fértil, que se define como mujeres premenopáusicas con una ligadura de trompas o histerectomía documentada,posmenopáusicas, considerado como 12 meses de amenorrea espontánea o si la mujer en edad fértil utiliza un método altamente eficaz para prevenir el embarazo (consulte Apéndice 1) durante la administración del fármaco y hasta 2 semanas después de la última dosis. La decisión de incluir o excluir mujeres en edad fértil se realizará según el criterio del investigador y de conformidad con la práctica local en relación con una adecuada anticoncepción.
3.Hospitalización para IMSEST o IMEST (IM de tipo 1 según la definición universal).
IMSEST que se presume como espontáneo (de tipo 1 según la definición universal) y se define como un malestar torácico isquémico (o equivalente) que se produce o persiste en reposo con, al menos, un episodio de >= 10 minutos de duración y se ve acompañado por una elevación diagnóstica de la concentración de troponina cardíaca por encima del límite superior del valor normal (límite de decisión de 99º percentil) según el laboratorio local, sin una elevación persistente del segmento ST . Si no se dispone de troponina cardíaca, la isoenzima creatina-cinasa MB (CK-MB) debe superar el límite superior del valor normal. El biomarcador debe mostrar un patrón ascendente y/o descendente cuando es posible realizar pruebas seriadas antes de la aleatorización.
IMEST se define como malestar torácico isquémico (o equivalente) que se produce o persiste en reposo con una elevación del segmento ST de, al menos, 0,1 mV en 2 o más derivaciones contiguas o un nuevo (o presumiblemente nuevo) bloqueo de la rama zquierda (y se presume un diagnóstico de IMEST.
NOTA: Los sujetos con manifestaciones clínicas o analíticas de SCA (p. ej., elevación del ST o aumento de las enzimas cardíacas) que se consideran secundarias a otras afecciones aparentes (como septicemia, anemia profunda, urgencia hipertensiva o insuficiencia cardíaca descompensada, embolia coronaria o disección; IM de tipo 2 según la definición universal) o que se sabe que se relacionan con el procedimiento (tipo 4, incluyendo trombosis de stent, o tipo 5) no se considera que cumplan estos criterios para IMSEST o IMEST.
4.Con los siguientes momentos de aparición de los síntomas:
IMSEST: presencia de síntomas isquémicos (? 5 minutos) en reposo en las 24 horas anteriores a la aleatorización (puede incluir el episodio actual objeto de valoración para su inclusión en el estudio).
IMEST: aparición de síntomas isquémicos del presente episodioen las 12 horas previas a la aleatorización.
5.Todos los sujetos deben presentar, al menos, uno de los siguientes factores pronósticos de riesgo cardiovascular adicionales:
a.Edad >= 60 años en el momento la aleatorización.
b.Antecedentes de IM documentado (IM de tipo 1 presunción o conocimiento antes del presente SCA por el que se valora su inclusión en el estudio
c.Antecedentes de IDAC con anterioridad a al presente SCA por el que se valora su inclusión en el estudio.
d.IMSEST con una nueva disminución de origen isquémico del segmento ST >= 0,1 mV en >= 2 derivaciones contiguas.
e.Diabetes mellitus que requiere farmacoterapia.
f.Arteriopatía clínicamente diagnosticada coexistente en, al menos, un territorio arterial periférico, que se define como:
-Antecedentes de accidente cerebrovascular isquémico cardioembólico (conocimiento o presunción), (confirmado mediante el historial clínico o los antecedentes) o
-antecedentes de arteriopatía periférica o presencia de la afección en la actualidad: claudicación intermitente actual con un índice tobillo-brazo <= 0,85 o antecedentes de implante de stent en arteria periférica o cirugía (incluyendo amputación por motivos vasculares).
Sujetos franceses: en Francia, únicamente los sujetos afiliados o beneficiarios de una categoría de la Seguridad Social se considerarán elegibles para la inclusión en este estudio.

E.4

Principal exclusion criteria

Subjects meeting any of the following criteria must not be enrolled in the study:
1. Unable to be randomized prior to coronary revascularization or fibrinolysis for the qualifying MI.
2. Current severe heart failure or shock (New York Heart Association [NYHA] class III or IV, or Killip class III or IV).
3. Ongoing clinical instability (e.g., hypotension requiring vasopressor or inotropic support, new stroke or transient ischemic attack [TIA], or recurrent sustained ventricular tachycardia).
4. History of chronic liver disease (defined below) or known to have current ALT ?2x upper limit of normal or total bilirubin >1.5x upper limit of normal or known history of hepatitis B or C.
Defined as known hepatic or biliary abnormalities (with the exception of Gilbert?s syndrome or asymptomatic gallstones). Such abnormalities include current drug therapy for the treatment of liver disease, unstable liver disease (defined by the presence of any of the following deemed by the investigator to be related to liver disease and not to other disease processes: ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice) or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
5.Known severe renal impairment.
Severe renal impairment is defined as receiving chronic dialysis or known estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at the time of randomization based on serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (see SPM).
6.Any condition, other than vascular disease, with life expectancy <1 year that might prevent the subject from completing the study.
7.Known active tuberculosis, HIV, active opportunistic or life threatening infections.
8.Vaccination with a live attenuated vaccine (see SPM) within 6 weeks of randomization.
9.Concomitant use of cytotoxic chemotherapy for cancer or known ongoing or anticipated use of chronic severe immunosuppressive agents as listed below:
?Chronic prednisone use >10 mg/day for >14 consecutive days.
?Currently receiving any systemic immunosuppressive therapy (See SPM for details).
10.Positive pregnancy test or is known to be pregnant or lactating.
All female subjects of childbearing potential must have a urine or serum ?-human chorionic gonadotropin [hCG] pregnancy test performed prior to randomization.
11.Known alcohol or drug abuse within the past 6 months.
12.Any current mental condition (psychiatric disorder, senility or dementia), which may affect study compliance or prevent understanding of the aims, investigational procedures or possible consequences of the study.
13.Use of another investigational product within 30 days or 5 half-lives (whichever is longer) or according to local regulations, or currently participating in a study of an investigational device. Subjects must be randomized only one time in this investigational study.
14.Anticipated inability to comply with any study procedures, including participation in study visits according to the visit schedule through 24 weeks.
15.Any other reason the investigator deems the subject to be unsuitable for the study.

French subjects: In France, a subject will be excluded if he/she has participated in any study using an investigational drug during the previous 30 days.

Los sujetos que cumplan cualquiera de los siguientes criterios no se incluirán en el estudio:
1. No se puede realizar la aleatorización antes de la revascularización coronaria o fibrinólisis para el IM por el que se está valorando la inclusión del paciente en el estudio.
2. Shock o insuficiencia cardiaca grave actual (Asociación del corazón de Nueva York [New York Heart Association, NYHA] de categoría III o IV, o Killip de categoría III o IV).
3. Inestabilidad clínica actual (p. ej., hipotensión que requiere vasopresor o tratamiento inotrópico, nuevo accidente cerebrovascular o accidente isquémico transitorio [AIT] o taquicardia ventricular prolongada recidivante).
4.Antecedentes de hepatopatía crónica (definida a continuación) o conocimiento de valores actuales de ALT >= 2 x límite superior del valor normal o bilirrubina total > 1,5 x límite superior del valor normal o antecedentes conocidos de hepatitis B o C.
Definido como anomalías hepáticas o biliares conocidas (con la excepción del síndrome de Gilbert o cálculos biliares asintomáticos). Dichas anomalías incluyen el tratamiento farmacológico actual de la hepatopatía, hepatopatía inestable (definida por la presencia de cualquiera de los siguientes y que el investigador considera relacionados con la enfermedad hepática y no con otros procesos: ascitis, encefalopatía, coagulopatía, hipoalbuminemia, varices esofágicas o gástricas o ictericia persistente) u otras anomalías hepáticas que, según la opinión del investigador, evitarían que el sujeto pudiera participar en el estudio.
5. Insuficiencia renal grave conocida.
La insuficiencia renal grave se define como un tratamiento con diálisis crónica o una tasa estimada de filtración glomerular (TFGe) conocida < 30 ml/min/1,73 m2 en el momento de la aleatorización en base a la creatinina sérica y la ecuación de colaboración epidemiológica para la enfermedad renal crónica (EPI-ERC) (véase el MPE).
6. Cualquier afección, distinta de enfermedad vascular, con una esperanza de vida < 1 año que pueda evitar que el sujeto complete el estudio.
7. Tuberculosis activa conocida, VIH, infecciones potencialmente mortales u oportunistas activas.
8. Vacunación con vacuna de virus vivos atenuados (véase el MPE) en las 6 semanas antes la aleatorización.
9. Uso concomitante de quimioterapia citotóxica para el cáncer o uso anticipado o actual en curso conocido de medicamentos inmunosupresores intensos crónicos enumerados a continuación:
- Uso de prednisona crónica > 10 mg/día durante > 14 días consecutivos.
- Administración actual de cualquier tratamiento inmunosupresor sistémico (véase MPE para más información).
10. Prueba de embarazo con resultado positivo o se sabe que está embarazada o en periodo de lactancia.
Todas las pacientes en edad fértil deben someterse a una prueba de embarazo de orina o beta-gonadotropina coriónica humana (GCH) en sangre antes de la aleatorización.
11. Alcoholismo o drogadicción conocidos en los últimos 6 meses.
12. Cualquier afección mental actual (trastornos psiquiátricos, senilidad o demencia) que pueda afectar al cumplimiento del estudio o evitar que se comprendan los objetivos, procedimientos de investigación o posibles consecuencias del estudio.
13. Uso de otro producto en investigación en 30 días o 5 semividas (lo que sea más largo) o según lo estipulado en la normativa local, o que ya esté participando en un estudio sobre un producto en investigación. En este estudio de investigación solo se realizará la aleatorización de los sujetos una vez.
14. Incapacidad anticipada para cumplir con cualquier procedimiento del estudio, incluyendo la participación en las visitas del estudio según el programa de visitas a lo largo de las 24 semanas.
15. Cualquier otro motivo que origine que el investigador considere que el sujeto no es adecuado para el estudio.
Sujetos franceses: en Francia, se excluirá a un sujeto si ha participado en un estudio que emplea un fármaco en investigación durante los 30 días anteriores.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the composite measure of adjudicated MACE that includes the time to first occurrence of CV death, MI, or SRI-UR.
If the effect of losmapimod on MACE shows a statistically significant benefit compared to placebo, then the analysis will proceed to testing the hypothesis for the principal secondary endpoint using a serial gate keeping procedure to account for multiplicity.

El criterio principal de valoración de la eficacia es el compuesto de MACE adjudicados que incluye el tiempo hasta la primera incidencia de muerte CV, IM o IRG-UR. En caso de que el efecto de losmapimod en MACE muestre un beneficio estadísticamente significativo en comparación con placebo, el análisis procederá a valorar la hipótesis para la principal variable secundaria utilizando un procedimiento de control de acceso seriado para tener en cuentala multiplicidad.

E.5.1.1

Timepoint(s) of evaluation of this end point

the principal analysis will be through 12 weeks, with additional analyses through 4 and 24 weeks

el análisis principal se hará a lo largo de las 12 semanas, con análisis adicionales a lo largo de 4 y 24 semenas.

E.5.2

Secondary end point(s)

-The principal secondary endpoint is the time to first occurrence of the composite of adjudicated CV death or MI.
Additional Secondary Endpoints:
-The composite of CV death, MI, or hospitalization for HF.
-The expanded composite of arterial CV events, defined as CV death, MI, SRI-UR, or stroke.
-The composite of coronary events (defined as CHD death, MI, SRI-UR, or any unplanned coronary artery revascularization).
Planned coronary artery revascularizations are those initial or staged interventions performed based on the initial qualifying ACS.
-The composite of CV death or hospitalization for HF
-The composite of CV death, MI or stroke.
-The composite of CV death, MI, SRI-UR, stroke or hospitalisation for HF
-The primary and principal secondary endpoints will be evaluated replacing CV death separately with CHD death (-Coronary MACE-) and all-cause death.
-The primary and principal secondary endpoints will be evaluated replacing all MI with Type 1 (spontaneous) MI.
-Individual components of the composite endpoints (including all-cause mortality).
-Definite or probable stent thrombosis.
-Any re-hospitalization within 30 days of discharge.

-El objetivo secundario principal es evaluar la eficacia de losmapimod en el momento de primera incidencia de IM o muerte CV adjudicada.
Objetivos secundarios adicionales:
-El compuesto de muerte CV, IM u hospitalización por insuficiencia cardíaca (IC).
-El compuesto ampliado de acontecimientos CV, definidos como muerte CV, IM, IRG-UR o accidente cerebrovascular.
-El compuesto de acontecimientos coronarios (definidos como muerte por ECC, IM, IRG-UR o cualquier revascularización de la arteria coronaria no planificada).
-Se consideran revascularizaciones de la arteria coronaria planificadas a aquellas intervenciones iniciales o estadificadas realizadas sobre el evento inicial de SCA que motivo a la inclusión en el estudio.El compuesto de muerte CV u hospitalización por IC.
-El compuesto de muerte CV, IM o accidente cerebrovascular.
-El compuesto de muerte CV, IM, IRG-UR, accidente cerebrovascular u hospitalización por IC.
-La variable primaria y la principal variable secundaria se evaluarán sustituyendo muerte CV por separado con muerte por ECC («MACE coronarios») y muerte por cualquier causa.
-El criterio secundario de valoración principal se valorará remplazando todos los IM con IM de tipo 1 (espontáneo).
-Componentes individuales de los criterios de valoración compuestos (incluyendo mortalidad por cualquier causa).
-Trombosis de stent definitiva o probable.
-Cualquier rehospitalización en los 30 días desde el alta hospitalaria.

E.5.2.1

Timepoint(s) of evaluation of this end point

the principal analysis will be through 12 weeks, with additional analyses through 4 and 24 weeks unless otherwise stated in the endpoint

el análisis principal se hará a lo largo de las 12 semanas, con análisis adicionales a lo largo de 4 y 24 semanas a menos que se indique lo contrario en cada variable.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarkers of CV risk.

biomarcadores de riesgo CV

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

371

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

Belgium

Bulgaria

Canada

Denmark

France

Greece

Italy

Netherlands

New Zealand

Norway

Romania

Slovakia

Sweden

Argentina

Australia

Brazil

Chile

Czech Republic

Estonia

Germany

Hong Kong

Hungary

India

Korea, Democratic People's Republic of

Spain

Thailand

Israel

Mexico

Peru

Philippines

Poland

Russian Federation

South Africa

Taiwan

Ukraine

United Kingdom

United States

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

LSLV August 10th 2018

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

13000

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

12500

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

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

11370

F.4.2.2

In the whole clinical trial

25500

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)

Subjects will be treated as deemed appropriate by the investigator following the end of the Treatment Phase. IP will not be available to subjects after the Treatment Phase (Week 12 visit + 2 weeks).
The investigator is responsible for ensuring that consideration has been given to the post-study care of the subject?s medical condition whether or not GSK is providing specific post-study treatment.

Después de finalizar la fase de tratamiento, el investigador tratará a los sujetos como se considere más apropiado. Los sujetos no tendrán acceso al PI después de la fase de tratamiento (visita de la Semana 12).
La responsabilidad de garantizar al sujeto el tratamiento adecuado la patología tras finalizar el estudio sin importar si GSK proporciona un tratamiento después de finalizar el estudio específico recaerá en el investigador.

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

2014-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-12-08

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Orphan Designation Number:
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