Clinical Trials Register

Summary
EudraCT Number:	2014-001485-99
Sponsor's Protocol Code Number:	BUL-2/EER
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:	2015-11-17
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

2014-001485-99

A.3

Full title of the trial

Double-blind, randomized, placebo-controlled, phase III study on the efficacy and tolerability of a 48-week treatment with two different doses of budesonide effervescent tablets vs. placebo for maintenance of clinico-pathological remission in adult patients with eosinophilic esophagitis

Estudio doble ciego, aleatorizado, controlado con placebo y de fase III sobre la eficacia y la tolerabilidad de un tratamiento de 48 semanas con dos dosis diferentes de comprimidos efervescentes de budesonida frente al placebo para el mantenimiento de la remisión clinicopatológica en pacientes adultos con esofagitis eosinofílica

A.3.1

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

Double-blind (neither physician nor patient knows of the actual treatment which can with or without active substance), randomized (patient will be allocated to a certain treatment group by chance), phase III study on the efficacy and tolerability of a 48-week treatment with two different doses of budesonide effervescent tablets in comparison with placebo for maintenance of clinico-pathological remission in adult patients with eosinophilic esophagitis

Ensayo doble ciego, aleatorizado, controlado con placebo y de fase III sobre la eficacia y la tolerabilidad de un tratamiento de 48 semanas con dos dosis diferentes de comprimidos efervescentes de budesonida frente a placebo para el mantenimiento de la remisión clínicopatológica en pacientes adultos con esofagitis eosinofílica

A.3.2

Name or abbreviated title of the trial where available

Maintenance of remission with budesonide effervescent tabl. vs. placebo in eosinophilic esophagitis

Mantenimiento de la remisión con comprimidos efervescentes de budesonida frente al placebo en la EEo

A.4.1

Sponsor's protocol code number

BUL-2/EER

A.5.4

Other Identifiers

Name:

EOS-2

Number:

Acronym

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	Dr. Falk Pharma GmbH
B.1.3.4	Country	Germany
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	Dr. Falk Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SERMES PLANIFICACION S.L
B.5.2	Functional name of contact point	Unidad de Puesta en Marcha
B.5.3	Address:
B.5.3.1	Street Address	C/ Rufino González 14, Esc.1ª-2ºD
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28037
B.5.3.4	Country	Spain
B.5.4	Telephone number	+349134756930
B.5.5	Fax number	+34917542721
B.5.6	E-mail	start-up@sermescro.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1181
D.3 Description of the IMP
D.3.1	Product name	1 mg budesonide effervescent tablet for orodispersible use
D.3.2	Product code	BUET 1mg
D.3.4	Pharmaceutical form	Effervescent 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	BUDESONIDE
D.3.9.1	CAS number	51333-22-3
D.3.9.4	EV Substance Code	SUB05955MIG
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	1
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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1181
D.3 Description of the IMP
D.3.1	Product name	0.5 mg budesonide effervescent tablet for orodispersible use
D.3.2	Product code	BUET 0.5 mg
D.3.4	Pharmaceutical form	Effervescent 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	BUDESONIDE
D.3.9.1	CAS number	51333-22-3
D.3.9.4	EV Substance Code	SUB05955MIG
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	0.5
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	Effervescent 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

Maintenance of remission in eosinophilic esophagitis

Mantenimiento de la remisión en esofagitis eosinofílica

E.1.1.1

Medical condition in easily understood language

Chronic allergic/immune-mediated inflammatory disease of the gullet in its remission phase

Enfermedad alérgica/ inmune inflamatoria del esófago en fase de remisión.

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10064220
E.1.2	Term	Eosinophilic esophagitis
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Double-blind phase:
- To assess the efficacy of a 48-week treatment with 2 x 0.5 mg/d or 2 x 1 mg/d budesonide effervescent tablets vs. placebo for the maintenance of clinico-pathological remission in adult patients with eosinophilic esophagitis (EoE).

Fase de doble ciego:
-Evaluar la eficacia de un tratamiento de 48 semanas con 2 x 0,5 mg/d o 2 x 1 mg/d de comprimidos efervescentes de budesonida frente a placebo para el mantenimiento de la remisión clinicopatológica en pacientes adultos con esofagitis eosinofílica (EE).

E.2.2

Secondary objectives of the trial

Double-blind phase:
- To study safety and tolerability in the form of adverse events and laboratory parameters
- To assess patients? quality of life.

Open-label re-induction phase:
- To study re-induction of clinical response in patients with a clinical or histological relapse or having experienced a food impaction which needed endoscopic intervention,

Open-label extension phase:
- To study maintenance of clinical remission in patients who completed the double-blind phase without a clinical or histological relapse

Exploratory:
-To study biomarkers in EoE.

Fase de doble ciego:
-Estudiar la seguridad y la tolerabilidad en forma de acontecimientos adversos y parámetros analíticos.
-Evaluar la calidad de vida del paciente.
Fase de reinducción y extensión abiertas:
-Estudiar la reinducción de la respuesta clínica en pacientes con recidiva clínica o histológica o que hayan experimentado impactación alimentaria que precisara intervención endoscópica,
-Estudiar el mantenimiento de la remisión clínica en pacientes que completaron la fase de doble ciego sin recidiva clínica o histológica.
Exploratorio:
-Estudiar los biomarcadores de la EE.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Signed informed consent,
- Male or female patients, 18 to 75 years of age,
- Confirmed clinico-pathological diagnosis of EoE according to established diagnostic criteria ,
- Clinico-pathological remission of EoE
- A documented trial with proton pump inhibitors (PPIs) in order to rule out PPI-responsive esophageal eosinophilia,
- Negative pregnancy test in females of childbearing potential at baseline visit

-firma del consentimiento informado;
-pacientes varones o mujeres de 18 a 75 años, ambos inclusive;
-diagnóstico clinicopatológico confirmado de EE según los criterios diagnósticos establecidos -remisión clinicopatológica de EE
-un ensayo documentado con inhibidores de la bomba de protones (IBP) para descartar eosinofilia esofágica
-Prueba de embarazo negativa en mujeres en edad fértil en la visita inicial

E.4

Principal exclusion criteria

- Clinical signs (i.e., acid regurgitation and/or heart burn) and/or endoscopic signs (at least Los Angeles Classification of Esophagitis Grade A) of gastroesophageal reflux disease (GERD),
- History of abnormal results in case of an optionally performed pH monitoring of the distal esophagus,
- Patients with PPI-responsive esophageal eosinophilia
- Achalasia, scleroderma esophagus, or systemic sclerosis,
- Other clinically evident causes than EoE for esophageal eosinophilia,
- Any concomitant esophageal disease and relevant gastro-intestinal disease (celiac disease, inflammatory bowel disease, oropharyngeal or esophageal bacterial, viral, or fungal infection [candida esophagitis]),
- Any relevant systemic disease (e.g., AIDS, active tuberculosis),
- If careful medical monitoring is not ensured: cardiovascular disease, diabetes mellitus, osteoporosis, active peptic ulcer disease, glaucoma, cataract, or infection,
- Liver cirrhosis or portal hypertension,
- History of cancer in the last five years,
- History of esophageal surgery at any time or of esophageal dilation procedures within the last 8 weeks prior to screening visit,
- Upper gastrointestinal bleeding within 8 weeks prior to screening visit,
- Existing or intended pregnancy or breast-feeding.

-signos clínicos (es decir, regurgitación ácida y/o acidez de estómago) y signos endoscópicos (al menos grado A según la clasificación de esofagitis de Los Angeles) de enfermedad de reflujo gastroesofágico (ERGE);
-antecedentes de resultados anómalos en caso de un control opcional del pH de la parte distal del esófago;
-pacientes con EES-IBP
-acalasia, esclerodermia esofágica o esclerosis sistémica;
-otras causas clínicamente evidentes distintas de la EE para la eosinofilia esofágica
-cualquier enfermedad esofágica concomitante y enfermedad gastrointestinal relevante (celiaquía, enfermedad inflamatoria intestinal, infección orofaríngea o esofágica bacteriana o vírica o infección fúngica no tratada o tratada de manera insuficiente [esofagitis por cándida])
-cualquier enfermedad sistémica relevante (p. ej., sida, tuberculosis activa)
-si el control médico minucioso no está garantizado: enfermedad cardiovascular, diabetes mellitus, osteoporosis, enfermedad por úlcera péptica activa, glaucoma, cataratas o infección.
-cirrosis hepática o hipertensión portal.
-antecedentes de cáncer en los últimos 5 años
-antecedentes de cirugía esofágica en cualquier momento o de procedimientos de dilatación esofágica en las 8 semanas previas a la visita inicial
-hemorragia gastrointestinal superior en las 8 semanas previas a la visita inicial
-embarazo existente o intención de quedarse embarazada o en período de lactancia

E.5 End points

E.5.1

Primary end point(s)

Rate of patients free of treatment failure after 48 weeks of treatment

-Tasa de pacientes sin fracaso del tratamiento después de 48 semanas de tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 48 weeks of double-blind phase

después de 48 semanas de la fase doble ciego

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
- Rate of patients with histological relapse at week 48 of the double-blind phase
- Rate of patients with a clinical relapse, have experienced a food impaction which needed endoscopic intervention, or needed an endoscopic dilation during the DB treatment phase

-tasa de pacientes con recidiva histológica en la semana 48 de DC
-tasa de pacientes con una recidiva clínica, que han experimentado impactación alimentaria que precisara intervención endoscópica o que precisaran una dilatación endoscópica durante la fase de tratamiento de DC;

E.5.2.1

Timepoint(s) of evaluation of this end point

after 48 weeks of double-blind phase

después de 48 semanas de la fase doble ciego

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

Abierto: 6 semanas de posible fase de inducción o re-inducción de la remisión; Semana 48 fase de ext

Open-label: possible 6-week phases for induction or re-induction of remission; 48w extension phase

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

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

Switzerland

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

Last Patient Out

Ultima visita del ultimo 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:

181

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

Yes

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

181

F.4.2.2

In the whole clinical trial

204

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)

Treatment after study end (i.e., after FU [follow-up visit]) is left to the investigator?s discretion. Patients being without clinical symptoms at the beginning of the follow-up phase should not receive additional concomitant treatment for EoE until completion of their follow-up visit. In cases, where a patient shows clinical symptoms when entering the follow-up phase, the patient could receive symptomatic treatment during the follow-up phase in the choice of the investigator.

El tratamiento después del final del estudio (es decir, después de la visita de seguimiento) se deja a eleccion del investigador. Los pacientes sin síntomas clínicos en el comienzo de la fase de seguimiento no deben recibir tratamiento concomitante adicional para EE hasta la finalización de su visita de seguimiento. En los casos en los que un paciente muestre síntomas clínicos al entrar en dicha fase, el paciente podría recibir tratamiento sintomático durante la fase a elección del 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

2016-01-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-12-11

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