Clinical Trials Register

Summary
EudraCT Number:	2016-003339-39
Sponsor's Protocol Code Number:	EHDA-01
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:	2017-04-07
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

2016-003339-39

A.3

Full title of the trial

A randomized, controlled and double-blind trial of intravenous azithromycin versus intravenous erythromycin as a single dose prior to endoscopy in upper gastrointestinal bleeding

Ensayo clínico controlado, aleatorizado y doble ciego de azitromicina intravenosa frente a eritromicina intravenosa dosis única previa a endoscopia en hemorragia digestiva alta

A.3.1

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

Trial: azithromycin versus erythromycin before endoscopy in upper gastrointestinal bleeding

Ensayo clínico: azitromicina frente a eritromicina antes de la endoscopia en hemorragia digestiva alta

A.4.1

Sponsor's protocol code number

EHDA-01

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	JOSÉ MARÍA PALAZÓN AZORÍN
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	ISABIAL-FISABIO
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	HOSPITAL GENERAL UNIVERSITARIO DE ALICANTE
B.5.2	Functional name of contact point	ÁREA DE ENSAYOS CLÍNICOS FARMACIA
B.5.3	Address:
B.5.3.1	Street Address	C/ PINTOR BAEZA, 12
B.5.3.2	Town/ city	ALICANTE
B.5.3.3	Post code	03010
B.5.3.4	Country	Spain
B.5.4	Telephone number	34965933314
B.5.5	Fax number	34965963306
B.5.6	E-mail	mluz.boquera@gmail.com

D. IMP Identification
D.IMP: 1
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	Erythromycin
D.3.4	Pharmaceutical form	Powder for solution for injection/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	ERYTHROMYCIN LACTOBIONATE
D.3.9.1	CAS number	3847-29-8
D.3.9.4	EV Substance Code	SUB01944MIG
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	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	Azithromycin
D.3.2	Product code	679927
D.3.4	Pharmaceutical form	Powder for solution for injection/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	AZITHROMYCIN DIHYDRATE
D.3.9.1	CAS number	83905-01-5
D.3.9.4	EV Substance Code	SUB16399MIG
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

Upper gastrointestinal haemorrhage

Hemorragia digestiva alta

E.1.1.1

Medical condition in easily understood language

Gastrointestinal bleeding

Sangrado digestivo

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	PT
E.1.2	Classification code	10046274
E.1.2	Term	Upper gastrointestinal haemorrhage
E.1.2	System Organ Class	10017947 - Gastrointestinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determine if intravenous azithromycin versus erythromycin as a single dose of 250 mg are equivalents (non-inferior) in quality of gastric mucosa visualization and obtaining a proper diagnostic (diagnostic efficiency) in patients with upper gastrointestinal bleeding and urgent endoscopy within 24 hours after admission.

Determinar si la administración de azitromicina vs eritromicina en dosis única de 250 mg vía intravenosa son equivalentes (no inferioridad) en la calidad de la visualización endoscópica (medida mediante la escala de Carbonell 2006) y obtención de un diagnóstico determinado (rendimiento diagnóstico) en pacientes con hemorragia digestiva alta y endoscopia de urgencias dentro de las 24 horas tras ingreso.

E.2.2

Secondary objectives of the trial

To assess the safety of the endoscopic and therapeutic procedure: incidence of complications related to endoscopy (such as perforation of the gastrointestinal tract, bronchoaspiration or death) and serious and unexpected adverse effects related to the treatment. To determine the proportion of patients with persistent or recurrent bleeding within 24 hours. To determine the need for a second endoscopy within 24 hours when the initial procedure was not diagnostic, including those reported as normal, bleeding due to non-obvious causes or as indeterminate, either due to poor preparation or active bleeding. To determine the proportion of patients undergoing surgical treatment after the endoscopy and to identify indications and surgical risk factors.
Measure the duration of the endoscopy and the units of transfused red blood cells within 48 hours.
To evaluate hospital mortality during admission and morbidity

Evaluar la seguridad del procedimiento endoscópico y terapéutico: incidencia de complicaciones relacionadas con la endoscopia (como perforación del tracto gastrointestinal, broncoaspiración o muerte) y efectos adversos graves e inesperados relacionados con el tratamiento. Determinar la proporción de pacientes con sangrado persistente o recurrente en 24 horas. Determinar la necesidad de una segunda endoscopia dentro de las 24 horas cuando el procedimiento inicial no fuera diagnóstico, incluyendo aquellos informados como normales, hemorragia por causas no evidentes o como indeterminados, debido a una mala preparación o con sangrado activo. Determinar la proporción de pacientes sometidos a tratamiento quirúrgico después de la endoscopia e identificar indicaciones y factores de riesgo quirúrgicos.
Medir la duración de la endoscopia y las unidades de concentrados de hematíes transfundidos dentro de las 48 horas.
Evaluar la mortalidad hospitalaria durante el ingreso y la morbilidad.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients older than 18 years with upper gastrointestinal bleeding defined as hematemesis, melena or coffee-ground hematemesist. Informed consent provided.

Pacientes mayores de 18 años que acudan a urgencias con diagnóstico clínico de hemorragia digestiva alta definida como hematemesis, melena o vómitos en “posos de café”. Habiendo firmado el consentimiento informado previamente.

E.4

Principal exclusion criteria

Allergy, interactions or contraindications to macrolides, previous administration of prokinetic agents in this episode, perforation or previous gastric surgery, history of cardiac arrhytnmias, acute myocardial infarction or cerebrovascular disease in the last 3 weeks, pregnancy or lactation.

Alergia, interacciones o contraindicaciones a macrólidos, uso de procinéticos en este ingreso, sospecha de perforación o cirugía gástrica, historia clínica de arritmias cardíacas, infarto agudo de miocardio (IAM) o enfermedad cerebrovascular en las últimas 3 semanas, embarazo y lactancia.

E.5 End points

E.5.1

Primary end point(s)

1. Diagnostic performance: having an etiologic diagnosis.
2. Quality of gastrointestinal tract visualization during endoscopy: Subjective criteria: stomach mucosa was entirely visualized or not based on the endoscopist’s judgment. Objective criteria: using a scale of 0 to 3: 0, insufficient preparation with large volume of red or black blood and/or adherent clots that could not be removed by lavage performed through the accessory channel of the endoscope; 1, poor preparation with a moderate volume of red or black blood and/or clots that could be fully removed during the examination by active lavage through the accessory channel; 2, good preparation with a small volume of red or black blood, but no clots; and 3, excellent preparation without blood or clots.

1. Rendimiento diagnóstico: obtención del diagnóstico etológico. Variable dicotómica y categórica, número de pacientes (%)
2. Calidad en la visualización durante la endoscopia: Criterio subjetivo: mucosa gástrica totalmente visible o no a juicio del endoscopista. Variable categórica, número de pacientes (%). Criterio objetivo: Escala puntuable de 0-3 en la que 0 se refiere a preparación insuficiente con gran volumen de sangre roja/negra y/o coágulos adheridos que no pueden ser eliminados por el canal accesorio del endoscopio; 1, preparación pobre con volumen moderado de sangre roja/negra y/o coágulos que pueden ser eliminados durante la prueba con lavado a través del canal accesorio del endoscopio; 2, buena preparación con volumen pequeño de sangre roja/negra, sin coágulos; 3, preparación excelente sin sangre ni coágulos. Variable categórica, número de pacientes (%).

E.5.1.1

Timepoint(s) of evaluation of this end point

For the two end points described above: in the first 24 hours after admission.

Para las dos variables principales descritas anteriormente: en las primeras 24 horas tras ingreso.

E.5.2

Secondary end point(s)

1. Duration of the endoscopy in minutes.
2. Need for second-look endoscopy within 24 hours after the initial endoscopy.
3. Hospital mortality.
4. Morbility as aspiration during endoscopy.
5. Bleeding or rebleeding within 24 hours after the initial procedure. 6. Number of transfused blood units during the first 48 hours.
7. Endoscopy-related complications.
8. Adverse effects related to erythromycin or azithromycin

1. Duración media de la endoscopia en minutos.
2. Necesidad de una segunda endoscopia en las 24 horas posteriores a la endoscopia inicial.
3. Mortalidad hospitalaria durante el ingreso.
4. Morbilidad en términos de aspiración, y si ésta se ha producido tras endoscopia bajo efecto de sedación o no.
5. Persistencia o recidiva de sangrado a las 24 horas del procedimiento inicial.
6. Tratamiento quirúrgico.
7. Unidades de concentrados de hematíes tras 48 horas
8. Complicaciones relacionadas con la endoscopia
9. Reacciones adversas a la perfusión de eritromicina o azitromicina.

E.5.2.1

Timepoint(s) of evaluation of this end point

It has been specified in every secondary end point: during endoscopy, at 24 hours of admission, at 48 hours of admission and before discharge of the hospital.

Especificado an cada uno de las variables secundarias: durante la endoscopia, a las 24 horas de ingreso, a las 48 horas de ingreso y en la visita de alta.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

LVLS

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:

120

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

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

120

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

2017-05-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-28

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

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