Clinical Trials Register

Summary
EudraCT Number:	2013-001498-25
Sponsor's Protocol Code Number:	CRLX030A2301
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:	2013-10-01
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

2013-001498-25

A.3

Full title of the trial

A multicenter, randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy, safety and tolerability of Serelaxin when added to standard therapy in acute heart failure patients

Estudio de fase III multicéntrico, aleatorizado, doble ciego, controlado con placebo para evaluar la eficacia, seguridad y tolerabilidad de serelaxina añadida a la terapia de referencia en pacientes con insuficiencia cardíaca aguda

A.3.1

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

Efficacy, safety and tolerability of Serelaxin when added to standard therapy in acute heart failure

eficacia, seguridad y tolerabilidad de serelaxina añadida a la terapia de referencia en pacientes con insuficiencia cardíaca aguda

A.3.2

Name or abbreviated title of the trial where available

Relax-AHF-2

A.4.1

Sponsor's protocol code number

CRLX030A2301

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	Novartis Farmacéutica, 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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmacéutica, S.A.
B.5.2	Functional name of contact point	Departamento Médico
B.5.3	Address:
B.5.3.1	Street Address	Gran Via de les corts Catalanes 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34900353036
B.5.5	Fax number	+34932479903
B.5.6	E-mail	eecc.novartis@novartis.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	serelaxin
D.3.2	Product code	RLX030
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
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	SERELAXIN
D.3.9.2	Current sponsor code	RLX030
D.3.9.4	EV Substance Code	SUB119779
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	1.0
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	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	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute heart failure

Insuficiencia cardiaca Aguda

E.1.1.1

Medical condition in easily understood language

Acute heart failure

Insuficiencia cardiaca Aguda

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

? Demonstrate that serelaxin is superior to placebo in reducing CV death in AHF patients during a follow-up period of 180 days.

Demostrar que serelaxina es superior al placebo para reducir la muerte CV en pacientes con ICA durante un período de seguimiento de 180 días.

E.2.2

Secondary objectives of the trial

Efficacy
? To demonstrate that serelaxin is superior to placebo in reducing the length of ICU and/or CCU stay during the index AHF hospitalization
? To demonstrate that serelaxin is superior to placebo in relieving signs and symptoms of congestion through Day 5
? To compare serelaxin to placebo in the changes of selected biomarkers in a subset of randomized patients
Safety
? To evaluate the safety and tolerability of intravenous serelaxin in AHF patients

Eficacia
? Demostrar que serelaxina es superior al placebo para reducir la duración de la permanencia en la UCI y/o UCC durante la hospitalización índice debido a ICA
? Demostrar que serelaxina es superior al placebo en aliviar los signos y síntomas de congestión hasta el Día 5
? Comparar la serelaxina frente al placebo en los cambios de biomarcadores seleccionados en un subgrupo de pacientes aleatorizados
Seguridad
? Evaluar la seguridad y tolerabilidad de serelaxina intravenosa en pacientes con ICA

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

-evaluate the impact of serelaxin on ECGs
-laboratory substudy: hematology, serum chemistry, urine dipstick
-biomarker substudy

-Evaluar impacto de serelaxina en ECG
-subestudio de laboratorio: hematología, bioquímica (suero), orina
- subestudio biomarcadores

E.3

Principal inclusion criteria

1. Written informed consent must be obtained before any study-specific assessment is performed
2. Male or female ?18 years of age, with body weight ?160 kg
3. Hospitalized for AHF; AHF is defined as including all of the following measured at any time between presentation (including the emergency department) and the end of screening:
?Dyspnea at rest or with minimal exertion
?Pulmonary congestion on chest radiograph
?BNP ?350 pg/mL or NT-proBNP ?1,400 pg/mL
4. Systolic BP ?125 mmHg at the start and at the end of screening
5. Able to be randomized within 16 hours from presentation to the hospital, including the emergency department
6. Received intravenous furosemide of at least 40 mg total (or equivalent) at any time between presentation (this includes outpatient clinic, ambulance, or hospital including emergency department) and the start of screening for the study for the treatment of the current acute HF episode.
7. Impaired renal function defined as an eGFR between presentation and randomization of ? 25 and ?75mL/min/1.73m2, calculated using the sMDRD equation

1. Hombres y mujeres ?18 años de edad que firmen el consentimiento informado, con un peso corporal ?160 kg
2. Hospitalizado debido a ICA; la ICA se define como incluir todo lo que se indica a continuación, medido en cualquier momento entre la presentación (incluido el servicio de urgencias) y el final de la selección:
? Disnea en reposo o por mínimo esfuerzo
? Congestión pulmonar o radiografía de tórax
? BNP ?350 pg/mL ó NT-proBNP ?1.400 pg/mL***
3. PA sistólica ?125 mmHg al inicio y al final de la selección y deterioro de la función renal definido como una TFGe*** entre la presentación y la aleatorización de ? 25 y ?75mL/min/1,73m2, calculada utilizando la ecuación sMDRD
4. Capaz de ser aleatorizado dentro de las 16 horas de haberse presentado en el hospital, incluido el servicio de urgencias**
5. Haber recibido furosemida intravenosa de al menos 40 mg en total (o equivalente) en cualquier momento entre la presentación (esto incluye servicio ambulatorio, ambulancia u hospital incluido el servicio de urgencias) y el inicio de la selección para el estudio para el tratamiento del episodio actual de IC aguda.
** La presentación comienza desde la situación que ocurra antes: o bien el (1) momento de la presentación ya sea en SU/SUH, UCI/UCC o en planta de hospital, (excluye los SMU u otros cuidados prehospitalarios); o bien el (2) momento del primer diurético de asa i.v. antes de la llegada al hospital (esto incluye servicio ambulatorio, ambulancia u hospital incluido el servicio de urgencias) para el episodio actual de IC aguda.
***Evaluada en base al laboratorio local

E.4

Principal exclusion criteria

1. Dyspnea primarily due to non-cardiac causes
2. Temperature >38.5°C (oral or equivalent) or sepsis or active infection requiring IV anti-microbial treatment
3. Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrollment. (Note that the diagnosis of acute coronary syndrome is a clinical diagnosis and that the sole presence of elevated troponin concentrations is not sufficient for a diagnosis of acute coronary syndrome, given that troponin concentrations may be significantly increased in the setting of AHF.)
4. AHF due to significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate <45 beats per minute, or atrial fibrillation/flutter with sustained ventricular response of >130 beats per minute
5. Patients with severe renal impairment defined as pre-randomization eGFR < 25 mL/min/1.73m2 calculated using the sMDRD equation, and/or those receiving current or planned dialysis or ultrafiltration
6. Significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area <1.0 cm2 or mean gradient >50 mmHg on prior or current echocardiogram), and severe mitral stenosis
7. Current (within 2 hours prior to screening) or planned (through the completion of study drug infusion) treatment with any IV vasoactive therapies, including vasodilators (including nesiritide), positive inotropic agents and vasopressors, or mechanical support (endotracheal intubation, mechanical ventilation; intra-aortic balloon pump or any ventricular assist device; hemofiltration, ultrafiltration or dialysis), with the exception of IV furosemide (or equivalent), or IV nitrates at a dose of ? 0.1 mg/kg/hour if the patient has a systolic BP >150 mmHg at screening.
8. Any major solid organ transplant recipient or planned/ anticipated organ transplant within 1 year
9. Major surgery, including implantable devices (e.g. ICD, CRT), or major neurologic event including cerebrovascular events, within 30 days prior to screening
10. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past year with a life expectancy less than 1 years
11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
12. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
13. Use of other investigational drugs within 30 days prior to screening
14. History of hypersensitivity to serelaxin
15. History of participating in serelaxin clinical studies
16. Inability to follow instructions or comply with follow-up procedures
17. Any other medical conditions that may put the patient at risk or influence study results in the investigator?s opinion, or that the investigator deems unsuitable for the study.
18. New exclusion criteria (hematocrit< 25% or blood transfusion in the prior 14 days or active, life-threatening GI bleeding)

1. Disnea principalmente debida a causas no cardíacas
2. Temperatura >38,5°C (oral o equivalente) o sepsis o infección activa que precise tratamiento antimicrobiano i.v.
3. Evidencia clínica de síndrome coronario agudo actualmente o en los 30 días previos al reclutamiento. (Téngase en cuenta que el diagnóstico de síndrome coronario agudo es un diagnóstico clínico y que la sola presencia de concentraciones elevadas de troponina no es suficiente para el diagnóstico de síndrome coronario agudo, dado que las concentraciones de troponina pueden aumentar significativamente en el contexto de la ICA.)
4. La ICA debida a arritmias importantes, que incluyan cualquiera de las siguientes: taquicardia ventricular sostenida, bradicardia con tasa ventricular sostenida <45 latidos por minuto, o fibrilación/aleteo auricular con respuesta ventricular sostenida de >130 latidos por minuto
5. Pacientes con insuficiencia renal severa definida como una TFGe en la prealeatorización < 25 mL/min/1,73m2 calculada utilizando la ecuación sMDRD, y/o pacientes que reciban diálisis actual o planificada o ultrafiltración
6. Obstrucción significativa del conducto de salida del ventrículo izquierdo, tales como miocardiopatía hipertrófica obstructiva o estenosis aórtica severa (es decir, área valvular aórtica <1,0 cm2 o gradiente medio >50 mmHg en ecocardiograma previo o actual), y estenosis mitral severa
7. Tratamiento actual (en las 2 horas previas a la selección) o planificado (hasta la finalización de la infusión de la medicación del estudio) con cualquier terapia vasoactiva i.v., incluidos vasodilatadores (incluida nesiritida), fármacos inotrópicos positivos y vasopresores, o soporte mecánico (intubación endotraqueal , ventilación mecánica; bomba de balón intraaórtico o cualquier dispositivo de asistencia ventricular; hemofiltración, ultrafiltración o diálisis), excepto por furosemida i.v. (o equivalente), o nitratos i.v. a una dosis de ? 0,1 mg/kg/hora si el paciente tiene una PA sistólica >150 mmHg en la selección.
8. Cualquier receptor de trasplante mayor de órgano sólido o trasplante de órgano planificado/ anticipado en el plazo de 1 año o cirugía mayor, incluidos dispositivos implantados (p.ej., DCI, TRC), o acontecimiento neurológico importante, incluidos los accidentes cerebrovasculares, en los 30 días previos a la selección
9. Antecedentes de enfermedad maligna de cualquier sistema orgánico (distinto a carcinoma basocelular localizado de piel), tratado o no tratado, en el último año con una esperanza de vida inferior a 1 año
10. Mujeres en edad fértil, definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas, salvo que estén utilizando un método de anticoncepción eficaz. Mujeres embarazadas o en período de lactancia, donde el embarazo se define como el estado de una mujer después de la concepción y hasta la finalización de la gestación, confirmado mediante el resultado positivo en la prueba de laboratorio de hCG.
11. ? Se ha añadido un criterio que excluye a los pacientes con Hematocrito <25%, o antecedentes de transfusión de sangre en los 14 días previos a la selección, o hemorragia GI potencialmente mortal active.

E.5 End points

E.5.1

Primary end point(s)

time to confirmed CV death

tiempo hasta muerte cardiovascular

E.5.1.1

Timepoint(s) of evaluation of this end point

throughout a period of 180 days

periodo de 180 días

E.5.2

Secondary end point(s)

Efficacy:
? Time to all-cause death
? Time to first occurrence of worsening of heart failure
? Length of total hospital stay for the index AHF hospitalization
? Time to first occurrence of the composite endpoint of CV death or rehospitalization due to heart failure/renal failure
? Length of ICU and/or CCU stay for the index AHF hospitalization
? Change from baseline in congestive signs and symptoms of HF through Day 5.
? Change from baseline in selected biomarkers in a subset of randomized patients
Safety:
? Physical examination
? Vital signs
? Height and weight
? Laboratory evaluations
? Electrocardiograph

? Tiempo hasta la muerte por todas las causas durante un período de seguimiento de 180 días
? Tiempo hasta la primera aparición de empeoramiento de la insuficiencia cardíaca* hasta el Día 5 (considerando la muerte en el período de 5 días como un acontecimiento de EIC)
? Duración de la permanencia en el hospital durante la hospitalización índice debido a ICA
? Tiempo hasta la primera aparición de la variable compuesta de muerte CV o rehospitalización debido a insuficiencia cardíaca/insuficiencia renal, durante un período de seguimiento de 180 días
? Duración de la permanencia en la UCI y/o UCC durante la hospitalización índice debido a ICA
? Cambio desde la visita basal en los signos y síntomas congestivos de IC hasta el Día 5
? Cambio respecto a la visita basal en biomarcadores seleccionados desde la visita basal hasta el Día 14 en un subgrupo de pacientes aleatorizados
? Exploración física
? Constantes vitales
? Altura y peso
? Evaluaciones de laboratorio
? Electrocardiografía

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout a period of 180 days except for:
"Time to first occurrence of worsening of heart failure" and "change from baseline in congestivesigns and symptoms of HF" where evaluation will be conducted through Day 5.
"Change from baseline in selected biomarkers" will be evaluated through Day 14.

durante 180 días excepto para :
Tiempo hasta la primera aparición de empeoramiento de la insuficiencia cardíaca* hasta el Día 5 (considerando la muerte en el período de 5 días como un acontecimiento de EIC) Cambio desde la visita basal en los signos y síntomas congestivos de IC hasta el Día 5
Cambio respecto a la visita basal en biomarcadores seleccionados desde la visita basal hasta el Día 14 en un subgrupo de pacientes aleatorizados

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

Yes

E.6.13.1

Other scope of the trial description

Biomarkers

biomarcadores

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

380

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

Argentina

Australia

Brazil

Chile

Colombia

Ecuador

Israel

Mexico

Norway

Peru

Russian Federation

Serbia

South Africa

Switzerland

United States

Croatia

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

until at least 513 total confirmed CV deaths occurs or earlier if a significant difference between two treatment arms for the number of CV deaths is achieved by crossing the pre-specified boundary at interim analysis

Hasta que ocurran al menos 513 muertes cardiovasculares confirmadas o antes si se consigue una diferencia significativa entre las dos ramas de tratamiento con respecto al nº de muertes cardiovasculares en el análisi intermedio

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:

1470

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

4905

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

240

F.4.2

For a multinational trial

F.4.2.1

In the EEA

3350

F.4.2.2

In the whole clinical trial

6375

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

Ninguno

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

2013-09-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-08-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-01-27

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