Clinical Trials Register

Summary
EudraCT Number:	2014-001485-99
Sponsor's Protocol Code Number:	BUL-2/EER
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-01-20
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

Italy - Italian Medicines Agency

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 clinicopathological remission in adult patients with eosinophilic esophagitis

Studio randomizzato in doppio cieco, controllato con placebo di fase III per la valutazione dell'efficacia e della tollerabilit¿ di un trattamento di 48 settimane con due diversi dosaggi di compresse effervescenti di budesonide rispetto al placebo per il mantenimento di una remissione clinico-istologica in pazienti adulti affetti da esofagite eosinofila

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

Studio in doppio-cieco (n¿ il medico n¿ il paziente conoscono il trattamento effettivo che pu¿ contenere o meno il principio attivo), randomizzato (al paziente sar¿ assegnato ad un certo gruppo di trattamento scelto casualmente), studio di fase III sull'
efficacia e tollerabilit¿ di un trattamento di 48 settimane con due diverse dosi di compresse effervescenti di Budesonide rispetto al placebo per
il mantenimento della remissione clinico-istologica nei pazienti adulti con esofagite eosinofila.

A.3.2

Name or abbreviated title of the trial where available

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

Mantenimento della remissione con compresse effervescenti di budesonide vs. placebo nell'esofagite e

A.4.1

Sponsor's protocol code number

BUL-2/EER

A.5.4

Other Identifiers

Name:

Acronym

Number:

EOS-2

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	Dr. Falk Pharma GmbH
B.5.2	Functional name of contact point	Dept.of Clinic. Res. & Development
B.5.3	Address:
B.5.3.1	Street Address	Leinenweberstr. 5
B.5.3.2	Town/ city	Freiburg
B.5.3.3	Post code	79108
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4976115140
B.5.5	Fax number	+497611514377
B.5.6	E-mail	zentrale@drfalkpharma.de

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	Compressa effervescente 1 mg di budesonide per uso orodispersibile
D.3.2	Product code	BUET 1 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.3.9.2	Current sponsor code	BUDESONIDE
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Compressa effervescente 0,5 mg di budesonide per uso orodispersibile
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.3.9.2	Current sponsor code	BUDESONIDE
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
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Mantenimento di remissione dell'esofagite eosinofila

E.1.1.1

Medical condition in easily understood language

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

Malattia infiammatoria cronica allergica / immune-mediata dell'esofago nella sua fase di remissione

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	20.1
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 in doppio cieco: Valutare l¿efficacia del trattamento della durata di 48 settimane con budesonide compresse effervescenti da 2x0,5 mg/die o da 2x1 mg/die rispetto a placebo per il mantenimento della remissione clinico-istologica in pazienti adulti affetti da esofagite eosinofila (EoE).

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 in doppio cieco:
-Studiare la sicurezza e la tollerabilit¿ in base agli eventi avversi e parametri di laboratorio,
-Valutare la qualit¿ di vita dei pazienti.
Fase di reinduzione in aperto: Studiare la reinduzione della risposta clinica in pazienti con recidiva clinica o istologica o che abbiano presentato episodio di impatto di bolo alimentare per cui sia stato necessario l¿intervento endoscopico.
fase di estensione in aperto: Studiare il mantenimento della remissione clinica nei pazienti che abbiano completato la fase in doppio-cieco senza ricadute cliniche o istologiche.
Esplorativo: Studiare i biomarkers associati all¿esofagite eosinofila.

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

-Sottoscrizione del consenso informato
-Pazienti di ambo i sessi di età compresa fra 18 e 75 anni
-Diagnosi di esofagite eosinofila confermata sia clinicamente che istologicamente in base ai criteri diagnostici
-Remissione clinico-istologica di esofagite eosinofila
- Evidenza di trattamento pregresso con inibitori della pompa protonica PPI al fine di escludere la presenza di eosinofilia esofagea responsiva ai PPI
- Risultato negativo al test di gravidanza eseguito nei soggetti di sesso femminile in età fertile alla visita basale

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 known or suspicion for relevant infectious diseases associated with clinical signs (e.g., AIDS defining disease, active tuberculosis, hepatitis B,
or hepatitis C)
- 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.

- Segni clinici (ovvero rigurgito acido e/o pirosi) e/o segni endoscopici (almeno di Grado A della classificazione Los Angeles Classification of Esophagitis) della malattia da reflusso gastroesofageo (GERD)
-Storia di alterazioni dei valori di pH rilevati durante un monitoraggio facoltativo dell’esofago distale
- Pazienti con PPI-REE
- Acalasia, sclerodermia all’esofago oppure sclerosi sistemica
-Evidenza clinica di altre cause della eosinofilia esofagea diverse dalla esofagite eosinofila
- Concomitanza di qualsiasi disturbo esofageo e patologia gastrointestinale rilevante (celiachia, malattia infiammatoria intestinale, infezione orofaringea o esofagea di natura batterica o virale, oppure infezione fungina non trattata oppure trattata in maniera non adeguata [esofagite da candida])
- Ogni nota o sospetta malattia infettiva rilevante associata a segni clinici (es. AIDS conclamato, tubercolosi attiva, epatite B o epatite C)
- Presenza di una delle seguenti patologie in assenza di un attento monitoraggio medico: malattie cardiovascolari, diabete mellito, osteoporosi, ulcera peptica in fase attiva, glaucoma, cataratta oppure infezione
- Cirrosi epatica oppure ipertensione portale
-Storia di cancro negli ultimi cinque anni
- Storia di intervento chirurgico a carico dell’esofago in qualsiasi momento, oppure di procedura di dilatazione dell’esofago nelle 8 settimane precedenti la visita di screening
-Sanguinamento a carico del tratto gastrointestinale superiore nelle 8 settimane precedenti la visita di baseline
- Gravidanza o allattamento al seno in atto o programmati

E.5 End points

E.5.1

Primary end point(s)

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

Tasso di pazienti che non hanno presentato fallimento terapeutico dopo 48 settimane di trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

after 48 weeks of double-blind phase

dopo 48 settimane di fase in doppio cieco

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
- Rate of patients with histological relapse at week 48 of the doubleblind 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

Endpoints secondari di efficacia:
- Tasso di pazienti con recidiva istologica alla settimana 48 della fase in doppio cieco
-Tasso di pazienti con recidiva clinica, che hanno presentato impatto del bolo alimentare con necessit¿ di intervento endoscopico o per cui ¿ stata necessaria la dilatazione endoscopica nel corso della fase di trattamento DB

E.5.2.1

Timepoint(s) of evaluation of this end point

after 48 weeks of double-blind phase

dopo 48 settimane di fase in doppio cieco

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

In aperto: possibili fasi di 6 sett per induzione o re-induzione remissione; fase estensione 48 sett

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

Information not present in EudraCT

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

Eswatini

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

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

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.

il trattamento dopo la fine dello Studio (es. dopo FU visit) ¿ a discrezione dello Sperimentatore. i pazienti senza sintomi clinici all'inizio della fase di FU non dovrebbero ricevere trattamenti concomitanti aggiuntivi per l'EoE fino al completamento della loro FU visit. Nei casi in cui un paziente mostri sintomi clinici all'ingresso della fase di FU, potr¿ ricevere un trattamento per la sintomatologia durante la fase di FU a giudizio dello Sperimentatore.

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

2017-09-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-06

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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