Clinical Trials Register

Summary
EudraCT Number:	2014-001433-83
Sponsor's Protocol Code Number:	IMPROVE-AHF
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:	2014-10-16
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

2014-001433-83

A.3

Full title of the trial

Loop Diuretics Dosage in Patients with Acute Heart Failure and Renal Failure: Conventional versus Carbohydrate Antigen 125 guided Strategy

Dosificación de los Diuréticos de Asa en Pacientes con Insuficiencia Cardiaca Aguda e Insuficiencia Renal: Estrategia Convencional versus Estrategia Guiada por los Niveles Plasmáticos del Antígeno Carbohidrato 125

A.3.1

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

Loop Diuretics Dosage in Patients with Acute Heart Failure and Renal Failure: Conventional versus Carbohydrate Antigen 125 guided Strategy

A.3.2

Name or abbreviated title of the trial where available

IMPROVE-AHF

A.4.1

Sponsor's protocol code number

IMPROVE-AHF

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	Fundación INCLIVA
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	Fundación INCLIVA
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	Fundación INCLIVA
B.5.2	Functional name of contact point	Marta Peiro
B.5.3	Address:
B.5.3.1	Street Address	Avenida Menendez Pelayo,4 acc
B.5.3.2	Town/ city	Valencia
B.5.3.3	Post code	46010
B.5.3.4	Country	Spain
B.5.4	Telephone number	34963862894
B.5.5	Fax number	34963987860
B.5.6	E-mail	incliva@incliva.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.2.1.2	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.3.1	Product name	Furosemida
D.3.2	Product code	Furosemida
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 Intrauterine use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FUROSEMIDE
D.3.9.1	CAS number	54-31-9
D.3.9.3	Other descriptive name	FUROSEMIDE
D.3.9.4	EV Substance Code	SUB07849MIG
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.2.1.2	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.3.1	Product name	Furosemida
D.3.2	Product code	Furosemida
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 Intrauterine use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FUROSEMIDE
D.3.9.1	CAS number	54-31-9
D.3.9.3	Other descriptive name	FUROSEMIDE
D.3.9.4	EV Substance Code	SUB07849MIG
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 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.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10000803
E.1.2	Term	Acute heart failure
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess whether a dosing strategy of loop diuretics guided by plasma levels of CA125 is superior to a strategy of standard dosage of loop diuretics regarding improving renal function and/or prevent renal deterioration at 24 and 72 hours after admission.

Evaluar si una estrategia de dosificación de furosemida intravenosa guiada por los
niveles plasmáticos del CA125 es superior a una estrategia de dosificación estándar de furosemida intravenosa en cuanto a mejorar la función renal y/o prevenir su deterioro a las 24 y 72 horas tras el ingreso.

E.2.2

Secondary objectives of the trial

1. Resolution of the breathlessness (changes in New York Heart Association functional class), signs of systemic congestion and patient global assessment (by visual analogue scale VAS) at 24 and 72 hours after admission.
2. Changes in plasma levels of natriuretic peptide (NT-proBNP) and high-sensitivity troponin 72 hours after admission.
3. Reduction of hospital stay and the time required for the passage of intravenous to oral diuretic administration.
4. Changes in systemic bioimpedance 72 hours after admission.
5. Clinical events: combined adverse event of death/rehospitalization for AHF at 30 days.
6. Parameters of renal function (creatinine, urea, NGAL and Cystatin C) at 30 days.

Comparar ambas estrategias en cuanto a:
1. Resolución de la disnea (cambios de la clase funcional de la NYHA), signos de congestión sistémica, y evaluación global del paciente (mediante la escala visual analógica VAS) a las 24 y 72 horas tras el ingreso.
2. Cambios en los niveles plasmáticos de péptidos natriuréticos (NT-ProBNP) y troponina de alta sensibilidad a las 72 horas.
3. Reducción de la estancia hospitalaria y el tiempo necesario para conseguir el paso de diuréticos intravenosos a su administración vía oral.
4. Cambios de la bioimpedancia sistémica a las 72 horas del ingreso.
5. Eventos clínicos: episodio adverso combinado de muerte/reingreso por insuficiencia cardiaca aguda a 30 días.
6. Parámetros de función renal (Creatinina, urea y NGAL y Cistatina C) a los 30 días.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Older than 18 years.
2. Presence of symptoms (dyspnea at rest or minimal exertion) and signs attributable to congestion (signs of congestion on chest radiography or presence of peripheral edema or ascites or jugular engorgement to 45 degrees or crackles on lung auscultation).
3. Elevated natriuretic peptides levels (NT-proBNP >1000 pg/ml or BNP >100 mg/dl).
4. Serum creatinine ?1.4 mg/dl on admission, provided that the estimated glomerular filtration rate is less than 60 ml/min/m2.
5. Intention to be treated with intravenous loop diuretics.
6. Participant or his legal representativeis willing and able to give informed consent for participation in the study.

1. Mayor de 18 años
2. Presencia de síntomas (disnea de reposo o a mínimos esfuerzos) y signos atribuibles a congestión (signos de congestión en la radiografía de tórax o presencia de edemas tibio-maleolares o ascitis o ingurgitación yugular a 45 grados o presencia de crepitantes en la auscultación pulmonar).
3. Elevación de péptidos natriuréticos (NTproBNP >1000 pg/ml o BNP >100 mg/dl).
4. Creatinina 1,4 mg/dl al ingreso, siempre que el FGE sea inferior a 60 ml/min/m2.
5. Intención de ser tratado con diuréticos de asa por vía intravenosa.
6. El paciente o su repesentante legal deberá de ser capaz de otorgar su consentimiento

E.4

Principal exclusion criteria

1. Life expectancy less than 6 months due to other comorbid conditions.
2. Cardiogenic shock.
3. Diagnosis of acute coronary syndrome in the previous 30 days.
4. Pregnancy at the time of inclusion.
5. Severe obstructive or restrictive lung disease.
6. Previously known Stage V chronic kidney disease (estimated glomerular filtration rate <15 ml/min/m2) or patient included in the dialysis program.
7. Participation in another randomized trial at the time of inclusion.
8. History of malignancy within the last 2-year
5.2.10. Temperature ?38°C or diagnosis of pneumonia.

1. Esperanza de vida inferior a 6 meses debido a otras condiciones comórbidas.
2. Shock cardiogénico.
3. Diagnóstico de síndrome coronario agudo en los 30 días previos.
4. Embarazo en el momento de la inclusión.
5. Enfermedad pulmonar obstructiva o restrictiva de grado severo.
6. Insuficiencia renal crónica estadio 5 (filtrado glomerular estimado <15 ml/min/m2) conocida previamente o paciente incluido en programa de diálisis.
7. Participación en otro ensayo clínico aleatorizado en el momento de la inclusión.
8. Temperatura +38°C o diagnóstico de neumonía.

E.5 End points

E.5.1

Primary end point(s)

The worsening and improvement of renal function is defined as an increase or decrease in the figures of creatinine ?0.3 mg/dl, respectively.

Empeoramiento o mejora de la Función renal definida como un incremento o descenso de los niveles de creatinina ?0.3 mg/dl, respectivamente.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 and 72 hours and 30 days

24, 72 horas y 30 dias

E.5.2

Secondary end point(s)

1. Functional class, defined by the New York Heart Association (NYHA) functional class.
2. The overall assessment of the patient will be assessed by visual analogue scale (VAS).
3. hsTnT and natriuretic peptides will be evaluated using commercial reagents as used in routine clinical practice.
3. Systemic bioimpedance will be assessed at admission and 72 hours using the bioelectrical impedance vector analysis (BIVA).
4. Clinical adverse events considered are death from any cause or readmission for AHF the first 30 days after admission.

1. Clase funcional, definido por la New York Heart Association (NYHA).
2. La evaluación global del paciente, escala analógica visual (VAS).
3. HsTnT y péptidos natriuréticos se evaluarán utilizando reactivos comerciales que se utilizan en la práctica clínica habitual.
4. Bioimpedancia sistémica se evaluará al ingreso y 72 horas a partir del análisis de bioimpedancia vectorial (BIVA).
5. Eventos adversos clínicos que se consideran son la muerte por cualquier causa o reingreso por ICA de los primeros 30 días después de la admisión.

E.5.2.1

Timepoint(s) of evaluation of this end point

24 and 72 hours and 30 days

24, 72 horas y 30 dias

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

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

Mismo medicamento diferente dosis

Same drug diferent dose

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit of the last subject undergoing the trial

Ultima visita del último paciente inlcuido en el ensayo

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:

140

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Due to the tipology of the Patients (with Acute Heart Failure), depend on the patient status, is possible that they can´t be able to give the consent personally

Debido a la tipología de los pacientes (con insuficiencia cardiaca aguda), depende del estado del paciente, es posible que no puedan ser capaces de dar el consentimiento personalmente

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

170

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

2015-01-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-12

P. End of Trial
P.	End of Trial Status	Completed

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