Clinical Trials Register

Summary
EudraCT Number:	2013-001852-36
Sponsor's Protocol Code Number:	CLOROTIC
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-11-12
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

2013-001852-36

A.3

Full title of the trial

Randomized, double blinded, multicenter study, to asses Safety and
Efficacy of the Combination of Loop With Thiazide-type Diuretics vs Loop
diuretics with placebo in Patients With Decompensated Heart Failure

Estudio aleatorizado, doble ciego, multicéntrico, para evaluar la eficacia y
la seguridad del tratamiento diurético combinado (diurético de asa e
hidroCLOROTiacida) comparado con diurético de asa y placebo en
pacientes con Insuficiencia Cardiaca descompensada.

A.3.1

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

Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics
in Patients With Decompensated Heart Failure (CLOROTIC)

Seguridad y eficacia de la combinación de diurético de asa con Tiazidas en
pacientes con insuficiéncia cardíaca descompensada

A.3.2

Name or abbreviated title of the trial where available

CLOROTIC

A.4.1

Sponsor's protocol code number

CLOROTIC

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01647932

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	Sociedad Española de Medicina Interna
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	Sociedad Española de Medicina Interna
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	Sociedad Española de Medicina Interna
B.5.2	Functional name of contact point	Sociedad Española de Medicina Inter
B.5.3	Address:
B.5.3.1	Street Address	Pintor Ribera, 3
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28016
B.5.3.4	Country	Spain
B.5.4	Telephone number	34972261800
B.5.5	Fax number	34972275235
B.5.6	E-mail	jctv5153@comg.cat

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	HIDROCLOROTIAZIDA KERN PHARMA 50 mg COMPRIMIDOS EFG
D.2.1.1.2	Name of the Marketing Authorisation holder	KERN PHARMA
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	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	HYDROCHLOROTHIAZIDE
D.3.9.1	CAS number	58-93-5
D.3.9.2	Current sponsor code	Sociedad Española de Medicina Interna
D.3.9.4	EV Substance Code	SUB08062MIG
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	50
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

Security and efficacy of Hidroclorothiazide plus Loop Diuretics in patients with descompensated heart failure

Seguridad y eficacia de Hidroclorotiacida con diureticos de Asa con pacientes de insuficiencia cardíaca desompensada

E.1.1.1

Medical condition in easily understood language

Security and efficacy of Hidroclorothiazide plus Loop Diuretics in patients with descompensated heart failure

Seguridad y eficacia de Hidroclorotiacida con diureticos de Asa con pacientes de insuficiencia cardíaca desompensada

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

Show that the strategy of adding a thiazide diuretic (HCTZ) to loop diuretic therapy in HF patients hospitalized for decompensation is more effective in improving congestive symptoms compared to loop diuretic therapy alone.

Demostrar que la estrategia de añadir un diurético tiacídico (HCTZ) al tratamiento con diurético de asa en pacientes con IC que ingresan por descompensación es más eficaz en la mejoría de los síntomas congestivos respecto al tratamiento con diurético de asa solo.

E.2.2

Secondary objectives of the trial

To determine whether there are patients whose clinical profile is associated with a better response to combined diuretic therapy and to predict those patients who will benefit from this treatment strategy.
assess the effects of combined diuretic therapy (loop diuretic plus HCTZ) compared with placebo plus loop diuretic on renal function in patients with decompensated HF.
assess the effects of combined diuretic therapy (loop diuretic plus HCTZ) compared with loop diuretic plus placebo on blood electrolytes (sodium and potassium serum) in patients with decompensated HF.
To evaluate the safety and tolerability of combined diuretic therapy (loop diuretic plus HCTZ) compared with loop diuretic plus placebo in patients with decompensated HF.
To assess mortality and readmissions within 90 days of patients with combined diuretic therapy (loop diuretic plus HCTZ) compared with loop diuretic plus placebo in patients with decompensated HF

Conocer si existen pacientes cuyo perfil clínico se asocie a una mejor respuesta al tratamiento diurético combinado y que permita predecir aquellos pacientes que van a beneficiar de esta estrategia de tratamiento.
Evaluar los efectos del tratamiento diurético combinado (diurético de asa más HCTZ(D+HCTZ)) en comparación con diurético de asa más placebo sobre la función renal en pacientes con IC descompensada.
Evaluar los efectos del tratamiento diurético combinado (D+HCTZ) en comparación con diurético de asa más placebo sobre los electrolitos en sangre (sodio y potasio séricos) en pacientes con IC descompensada.
Evaluar la seguridad y tolerabilidad del tratamiento diurético combinado (D+HCTZ) en comparación con diurético de asa más placebo en pacientes con IC descompensada.
Evaluar la mortalidad y los reingresos a los 90 días de los pacientes con tratamiento diurético combinado (D+HCTZ) en comparación con diurético de asa más placebo en pacientes con IC descompensada.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients eligible for inclusion in this study must meet all the following criteria:
Male or female patients aged less than 18 years old.
Patients with chronic HF prior (from any cause and regardless of the degree of ventricular dysfunction) according to the criteria of the European Society of Cardiology [15] admitted for decompensation defined as presence of at least one symptom (dyspnea, orthopnea or edema) and a sign (rales on auscultation, third heart sound, peripheral edema, ascites, pulmonary vascular congestion on chest radiograph)
Patients should be taking loop diuretic orally chronically (at least one month).
Previous doses of oral diuretics should be: between 80 and 160 oral furosemide and equivalent doses for other loop diuretics (torasemide 20mg and 1 mg of bumetanide are considered equivalent to 40 mg of furosemide).
Patients must give their written informed consent to participate in the study and before they do any of the study-related evaluations.

Los pacientes elegibles para ser incluidos en este estudio han de cumplir todos los criterios siguientes:
Pacientes hombres o mujeres con edad igual o superior a 18 años de edad.
Pacientes con IC crónica previa (de cualquier etiología e independientemente del grado de disfunción ventricular) según los criterios de la Sociedad Europea de Cardiología [15] que ingresan por descompensación definida como presencia de al menos un síntoma (disnea, ortopnea o edema) y un signo (crepitantes en auscultación, tercer ruido cardiaco, edema periférico, ascitis, congestión vascular pulmonar en la radiografía de tórax)
Los pacientes deben estar tomando diurético de asa por vía oral de forma crónica (como mínimo un mes).
Las dosis previas de diurético de asa por vía oral deben ser las siguientes: entre 80 y 160 de furosemida por vía oral y dosis equivalentes para los otros diuréticos de asa (20mg de torasemida y 1mg de bumetanida se consideran equivalentes a 40mg de furosemida).
Los pacientes deberán otorgar su consentimiento informado por escrito para participar en el estudio y antes de que se realice ninguna de las evaluaciones relacionadas con el estudio.

E.4

Principal exclusion criteria

Patients who have any of the following criteria may not participate in the study:
BNP plasma levels of <100 pg / ml, or NT-pBNP <300 pg / ml
Patients previously diagnosed with severe aortic stenosis
Patients with decompensated edematous etiology other than the CI right HF secondary to pulmonary hypertension and / or pulmonary embolism, liver cirrhosis, nephrotic syndrome, etc..
Patients with hyponatremia at the time of selection: be excluded any value of Hippo + that is symptomatic or when sodium (Na +) levels less than or equal to 125mEq / L.
Patients with acute coronary syndrome at the time of admission.
Patients in cardiogenic xoc situation at the time of admission.
Patients requiring admission to the Intensive Care Unit / Coronary Care Unit
Patients requiring treatment with vasoactive drugs (dopamine, dobutamine, norepinephrine) at admission. It allows patients to receive treatment with vasoactive drugs on admission (at the discretion of the attending physician) and it will not be a reason by itself sufficient for removal of the patient from the study.
Patients requiring renal replacement therapy: hemodialysis, hemodiafiltration, ultrafiltration, etc..
Patients with a life expectancy less than 6 months at the time the income is not attributable to heart failure
Patients treated with HCTZ or other thiazide diuretic during the month prior to admission.
Patients treated with aldosterone antagonists initiated within 30 days of entry. Allowing the patient is taking aldosterone if taken stably for more than one month.
Pregnant or breastfeeding.
History or evidence of drug or alcohol abuse in the last 12 months.
Any surgical or medical condition which in the opinion of the investigator, may put the patient at a higher risk because of their participation in the study, or is likely to prevent the patient meets the requirements of the study or the end of the study.
History of noncompliance with medical regimens or who is not willing meet the study protocol.
Any condition that, in the opinion of the investigator, could jeopardize the evaluation of the efficacy or safety.
Lack of acceptance by the patient to participate in the study.
Having participated in other clinical trials during the previous 3 months

Los pacientes que presenten cualquiera de los siguientes criterios no podrán participar en el estudio:
Niveles plasmáticos de BNP < 100 pg/ml o de NT-pBNP < 300 pg/ml
Pacientes previamente diagnosticados de estenosis aórtica severa
Pacientes con descompensación edematosa de etiología distinta a la IC: IC derecha secundaria a hipertensión pulmonar y/o tromboembolismo pulmonar, cirrosis hepática, síndrome nefrótico, etc.
Pacientes con hiponatremia en el momento de la selección: será excluido cualquier valor de hipoNa+ que sea sintomática o cuando el sodio (Na+) sérico sea inferior o igual a 125mEq/L.
Pacientes con síndrome coronario agudo en el momento del ingreso.
Pacientes en situación de shock cardiogénico en el momento del ingreso.
Pacientes que requieran ingreso en la Unidad de Cuidados Intensivos / Unidad Coronaria
Pacientes que requieran tratamiento con drogas vasoactivas (dopamina, dobutamina, noradrenalina) al ingreso. Se permite que los pacientes reciban tratamiento con drogas vasoactivas durante el ingreso (a criterio del médico responsable) y este no será un motivo por si solo suficiente para la retirada del paciente del estudio.
Pacientes que requieran terapias de sustitución renal: hemodiálisis, hemodiafiltración, ultrafiltración, etc.
Pacientes con expectativa de vida inferior a 6 meses en el momento del ingreso no atribuible a la insuficiéncia cardíaca.
Pacientes bajo tratamiento con HCTZ u otro diurético tiacídico durante el mes previo al ingreso.
Pacientes bajo tratamiento con antialdosterónicos iniciados en los 30 días previos al ingreso. Se permite que el paciente esté tomando antialdosterónicos si los toma de forma estable desde hace más de un mes.
Mujeres embarazadas o en período de lactancia.
Antecedentes o indicios de toxicomanía o alcoholismo en los últimos 12 meses.
Cualquier condición quirúrgica o médica que, en opinión del Investigador, pueda poner al paciente en una situación de mayor riesgo debido a su participación en el estudio, o que es probable que impida que el paciente cumpla los requisitos del estudio o que finalice el estudio.
Antecedentes de incumplimiento de los regímenes médicos o que no esté dispuesto/a a cumplir el protocolo del estudio.
Cualquier condición que, en opinión del Investigador, pueda poner en peligro la evaluación de la eficacia o seguridad.
Falta de aceptación por parte del paciente para participar en el estudio.
Haber participado en otros ensayos clínicos durante los 3 meses previos.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variables are the following:
Weight Loss: daily weight loss (mean in kg) and total weight loss (from baseline to visit 6)
24 hour diuresis: quantification of diuresis in 24 hours (average cc)
Changes in signs and symptoms of heart failure: NYHA functional class and dyspnea scales (from baseline to visit 6).

Las variables de eficacia principal son las siguientes:
Pérdida de peso: pérdida de peso diaria (media en Kg) y pérdida total de peso (desde la situación basal a la visita 6)
Diuresis de 24 horas: cuantificación de la diuresis en 24 horas (media en cc)
Cambios en los signos y síntomas de insuficiencia cardiaca: clase funcional de la NYHA y escalas de disnea (desde la situación basal a la visita 6).

E.5.1.1

Timepoint(s) of evaluation of this end point

from baseline to visit 6

desde la situación basal a la visita 6

E.5.2

Secondary end point(s)

Changes in renal function as measured by changes in eGFR and serum creatinine from baseline to visit 6.
Changes in blood electrolytes (sodium and potassium) from baseline visit to visit 6
Changes from baseline to visit 6 in the amount of sodium and potassium in urine and the ratio of urine albumin and creatinine

Cambios en la función renal medida mediante los cambios en la TFGe y en la creatinina sérica desde la basal hasta la visita 6.
Cambios en los electrolitos en sangre (sodio y potasio) desde la visita basal hasta la visita 6
Cambios desde la basal hasta la visita 6 en la cifra de sodio y potasio en orina y en la relación de albúmina y creatinina en orina

E.5.2.1

Timepoint(s) of evaluation of this end point

from baseline to visit 6

desde la basal hasta la visita 6

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

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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)

Yes

E.8.2.2

Placebo

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

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

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

Follow-up visit within 90 days of discharge

Visita de seguimiento a los 90 días del alta hospitalaria

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:

354

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

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

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

400

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-01-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-09

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

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