Clinical Trials Register

Summary
EudraCT Number:	2018-002617-35
Sponsor's Protocol Code Number:	BUL-5/ESD
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2019-05-28
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

Germany - BfArM

A.2

EudraCT number

2018-002617-35

A.3

Full title of the trial

Double-blind, randomised, placebo-controlled, phase IIa trial on the efficacy and tolerability of an 8-week treatment with two different doses of budesonide orodispersible tablets vs. placebo for prevention of oesophageal strictures in adult patients after endoscopic submucosal dissection

Doppelblinde, randomisierte, Plazebo-kontrollierte Phase-lla-Studie zur Untersuchung der Wirksamkeit und Verträglichkeit einer 8-
wöchigen Behandlung mit zwei verschiedenen Dosierungen von Budesonid-Schmelztabletten im Vergleich zu Plazebo zur Verhinderung ösophagealer Strikturen bei erwachsenen Patienten nach endoskopischer Submukosadissektion

A.3.1

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

Double-blinded (treatment group unknown to physician and patient), randomised (treatment group allocated by chance) phase II trial on the efficacy and tolerability of an 8 week treatment with two different doses of budesonide tablets dissolving in the mouth compared to placebo (medication without active substance), for prevention of constrictions of the oesophagus in adult patients after removal of cancer tissue using an endoscopic surgery technique

Doppelt verblindete (weder Arzt noch Patient kennen die Behandlungsgruppe), randomisierte (Behandlungsgruppe per Zufallsprinzip) Phase II Studie zur Wirksamkeit und Verträglichkeit einer 8-wöchigen Behandlung zweier Dosierungen einer sich im Mund auflösenden Budesonid-Tablette im Vergleich zu Plazebo (Scheinmedikament), zur Verhinderung von Verengungen der Speiseröhre bei erwachsenen Patienten nach Entfernung von Speiseröhrenkrebsgewebe mit Hilfe einer endoskopischen Operationstechnik

A.3.2

Name or abbreviated title of the trial where available

Budesonide orodispersible tablets vs. placebo to prevent oesophageal strictures after ESD

A.4.1

Sponsor's protocol code number

BUL-5/ESD

A.5.4

Other Identifiers

Name:

PEGASUS-1

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	Dr. Falk Pharma GmbH
B.5.2	Functional name of contact point	Dept. of Clin. 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	Yes
D.2.1.1.1	Trade name	Jorveza 1 mg orodispersible tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Dr. Falk Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Orodispersible 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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	2 mg budesonide orodispersible tablet
D.3.2	Product code	BUL 2 mg
D.3.4	Pharmaceutical form	Orodispersible 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	2
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	Orodispersible 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

Prevention of oesophageal strictures in adult patients after endoscopic submucosal dissection

Verhinderung von Strikturen der Speiseröhre bei erwachsenen Patienten nach endoskopischer Submukosadissektion

E.1.1.1

Medical condition in easily understood language

Prevention of strictures of the oesophagus in adult patients after removal of cancer tissue from the oesophagus using an endoscopic surgery technique

Verhinderung von Verengungen der Speiseröhre bei erwachsenen Patienten, bei denen Gewebe eines Speiseröhrenkrebs mit Hilfe einer endoskopischen Operationstechnik entfernt wurde

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	25.1
E.1.2	Level	LLT
E.1.2	Classification code	10030186
E.1.2	Term	Oesophageal squamous cell carcinoma NOS
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10030137
E.1.2	Term	Oesophageal adenocarcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10004137
E.1.2	Term	Barrett's oesophagus
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

• To assess the efficacy of eight weeks treatment with 2 x 1 mg/day or 2 x 2 mg/day budesonide orodispersible tablets vs. placebo for prevention of oesophageal strictures after endoscopic submucosal dissection.

• Bewertung der Wirksamkeit einer achtwöchigen Behandlung mit Budesonid-Schmelztabletten in einer Dosierung von 2 x 1 mg/Tag oder 2 x 2 mg/Tag versus Plazebo zur Prävention von ösophagealen Strikturen nach einer endoskopischen Submukosadissektion.

E.2.2

Secondary objectives of the trial

• To study safety and tolerability of budesonide orodispersible tablets vs. placebo by means of adverse events and laboratory parameters.
• To assess patients’ quality of life.

• Untersuchung der Sicherheit und Verträglichkeit von Budesonid-Schmelztabletten versus Plazebo anhand von unerwünschten Ereignissen und Laborparametern.
• Beurteilung der Lebensqualität der Patienten

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Signed informed consent;
• Male or female patients, 18 to 85 years of age;
• Estimated life expectancy of at least one year (not applicable in Portugal);
• ECOG Performance Status of ≤ 2 at the randomisation visit (i.e. after the ESD-procedure);
• a) Biopsy proven or endoscopically suspect oesophageal SCC and/or high grade dysplasia in a focal lesion of the squamous epithelium, treated with ESD;
or
b) Biopsy proven or endoscopically suspect BE-HGD or EAC, treated with ESD;
• Mucosal defect after ESD of
a) ≥ 50% oesophageal circumference in a patient with SCC,
or
b) ≥ 75% oesophageal circumference in a patient with BE-HGD or EAC;
• Negative pregnancy test in females of childbearing potential at the screening visit.

•Unterzeichnete Einwilligungserklärung;
• Männliche oder weibliche Patienten im Alter zwischen 18 und 85 Jahren;
• Geschätzte Lebenserwartung von mindestens einem Jahr (entfällt in Portugal);
•ECOG-Leistungsstatus von ≤ 2 beim Randomisierungstermin (d. h. nach der ESD);
• a) Ein durch Biopsie belegter oder endoskopischer Verdacht auf ein ösophageales Plattenepithelkarzinom und/oder hochgradige Dysplasie in einer fokalen Läsion des squamösen Epithels, behandelt mit ESD;
b) Ein durch Biopsie belegter oder endoskopischer Verdacht auf BE-HGC oder EAC, behandelt mit ESD;
• Schleimhautdefekt nach ESD mit einer Ausdehnung von
a) ≥ 50 % des Umfangs des Ösophagus bei einem Patienten mit SCC
b) ≥ 75 % des Umfangs des Ösophagus bei einem Patienten mit BE-HGD oder EAC;
•Negativer Schwangerschaftstest bei Frauen im gebärfähigen Alter bei der Screening Visite;

E.4

Principal exclusion criteria

•Any prior or intended chemotherapy for oesophageal cancer;
• Any prior ESD in the area where ESD will be done;
• Any prior or intended oesophageal surgery or surgery for the mediastinum, endoscopic mucosal resection (EMR), or radio frequency ablation (RFA), in the area where ESD will be done;
• Evidence of regional lymph node metastases or distant metastases prior to ESD;
• Any prior or intended radiotherapy which involves or affects the area of ESD during the last 5 years;
•Any prior endoscopic dilation for oesophageal stenosis which involves or affects the area of ESD during the last 5 years;
• Any other concomitant oesophageal disease;
•Any severe concomitant disease, which in the opinion of the investigator might have an influence on the patient's compliance or the interpretation of the results, or any disorder which in the opinion of the investigator might affect the patient's safety;
• Any systemic therapy for any reason that may affect assessment of primary or secondary endpoints.

• Jede vorherige oder geplante Chemotherapie wegen eines Speiseröhrenkarzinoms;
• Jede frühere ESD in dem Bereich, in dem die ESD durchgeführt werden wird;
• Jeder frühere oder geplante chirurgische Eingriff an der Speiseröhre oder chirurgischer Eingriff am Mediastinum, endoskopische Mukosaresektion (EMR) oder Radiofrequenzablation (RFA) im Bereich, in dem die ESD durchgeführt werden wird;
•Nachweis von regionalen Lymphknotenmetastasen oder Fernmetastasen vor der ESD;
• Jede frühere oder geplante Strahlentherapie, die den Bereich, in dem die ESD durchgeführt werden wird, miteinbezieht oder beeinträchtigt, in den letzten 5 Jahren;
• Jede frühere endoskopische Dilatation einer ösophagealen Stenose, die den Bereich der ESD miteinbezieht oder beeinträchtigt, in den letzten 5 Jahren
• Jede andere gleichzeitig bestehende Erkrankung der Speiseröhre;
• Jegliche schwere gleichzeitig auftretende Erkrankung, die nach Ansicht des Prüfarztes die Compliance des Patienten oder die Interpretation der Ergebnisse beeinflussen könnte, und alle Erkrankungen, die nach Ansicht des Prüfarztes die Sicherheit des Patienten beeinträchtigen könnten;
• Jede systemische Therapie aus irgendeinem Grund, die die Beurteilung der primären oder sekundären Endpunkte beeinflussen kann.

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoint:
• Percentage of patients free of strictures at visit week 8.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 8 weeks of double-blind phase

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
• Number of endoscopic dilations per patient during the DB treatment
phase.
• Percentage of patients free of strictures until the FU visit.

E.5.2.1

Timepoint(s) of evaluation of this end point

Endpoint 'Number of endoscopic dilations per patient during the DB
treatment phase': after 8 weeks of double-blind phase

Endpoint 'Percentage of patients free of strictures until the FU visit': at
follow-up visit

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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)

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

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

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:

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

F.4.2.2

In the whole clinical trial

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

2019-06-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-08-20

P. End of Trial
P.	End of Trial Status	Restarted

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