Clinical Trials Register

Summary
EudraCT Number:	2018-000415-25
Sponsor's Protocol Code Number:	PROSPER
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-06-21
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

Germany - BfArM

A.2

EudraCT number

2018-000415-25

A.3

Full title of the trial

PANCREATIC RESECTION WITH PERIOPERATIVE OFF-LABEL STUDY OF PROPRANOLOL AND ETODOLAC – A PHASE II RANDOMIZED TRIAL

PROSPER Studie – Randomisierte, doppelt verblindete, Placebo-kontrollierte, Phase II – Studie zum Off-Label Einsatz von Etodolac und Propranolol im perioperativen Setting von Pankreaskarzinomoperationen

A.3.1

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

Randomized phase II trial with propranolol and etodolac for patients with tumor resection of the pancreatic head.

Randomisierte Phase II–Studie zur perioperativen Off-Label Behandlung mit Propranolol und Etodolac im Rahmen von Bauchspeicheldrüseneingriffen.

A.4.1

Sponsor's protocol code number

PROSPER

A.5.4

Other Identifiers

Name:

German Clinical Trials Register

Number:

DRKS00014054

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	University Hospital Heidelberg
B.1.3.4	Country	Germany
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	Het Anti-Kankerfonds, Anticancer Fund
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Study Center of the German Surgical Society
B.5.2	Functional name of contact point	SDGC
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 130.3
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	496221566980
B.5.5	Fax number	4962215633850
B.5.6	E-mail	sdgc@med.uni-heidelberg.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	Dociton 10 mg film-coated tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	mibe GmbH Arzneimittel
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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.2.1.1.1	Trade name	Todolac
D.2.1.1.2	Name of the Marketing Authorisation holder	Norpharma A/S, Frydenlundsvej 30, 2950 Vedbæk
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Todolac
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
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

Patients with pancreatic carcinoma treated by pancreatoduodenectomy.

Pankreatoduodenektomie aufgrund eines Pankreaskarzinoms

E.1.1.1

Medical condition in easily understood language

Patients with tumor resection of the pancreatic head

Patienten, denen ein Tumor des Pankreaskopfes entfernt werden soll.

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10033659
E.1.2	Term	Pancreatoduodenectomy
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of the trial is assessment of safety for the perioperative use of propranolol and etodolac in patients with resectable cancer of the pancreatic head planned for elective pancreatoduodenectomy.

Das Hauptziel der Studie ist die Beurteilung der Sicherheit, für die perioperative Verwendung von Propranolol und Etodolac bei Patienten, die an einem resezierbaren Karzinom des Pankreaskopfes erkrankt sind.

E.2.2

Secondary objectives of the trial

The secondary objectives of the trial are to assess feasibility and to generate first efficacy data for the perioperative use of propranolol and etodolac in patients with resectable cancer of the pancreatic head planned for elective pancreatoduodenectomy.

Die weiteren Ziele der Studie sind die Untersuchung der Machbarkeit und Wirksamkeit für die perioperative Verwendung von Propranolol und Etodolac bei Patienten, die an einem resezierbaren Karzinom des Pankreaskopfes erkrankt sind.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

· Patients planned for elective pancreatoduodenectomy
· Patients eligible for perioperative therapy with propranolol / etodolac

· Patienten, bei denen eine elektive Pankreatoduodenektomie geplant ist.
· Patienten, die für eine präoperative Behandlung mit Propranolol und Etodolac geeignet sind.

E.4

Principal exclusion criteria

· Prior / concurrent therapy with beta-blockers, Cox-2 inhibitors or
Etodolac
· Known allergies to beta-blockers, Cox-2 inhibitors or Etodolac
· Patients with a known long-term medication that may cause severe
interactions with propranolol / etodolac

· vorherige oder konkurrierende Therapie mit beta-Blockern, Cox-2-Inhibitoren und Etodolac
· bekannte Allergien auf beta-Blocker, Cox-2 Inhibitoren und Etodolac
· Patienten mit bekannter Langzeitmedikation, die zu schweren Wechselwirkungen mit Propranolol und Etodolac führen können.

E.5 End points

E.5.1

Primary end point(s)

Safety endpoints:
• Rates of severe adverse events and severe adverse drug reactions
• Mortality at 30 and 90 days postoperatively
• Pancreas-associated morbidity (pancreatic fistula, delayed gastric
emptying, postoperative pancreatic hemorrhage, biliary
leakage, fluid collection/abscess)

Endpunkte zur Sicherheit:
• Raten von schwerwiegenden unerwünschten Ereignissen und schwerwiegenden unerwünschten Arzneimittelwirkungen
• Mortalität 30 und 90 Tage postoperativ
• Pankreas-assoziierte Morbidität (Fistel, verzögerte Magen-Entleerung, postoperative Pankreasblutung, Gallenleckage, Flüssigkeitsansammlung / Abszess)

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 2: one day before Operation
Visit 3: day of surgery
Visit 4: post-operative day (POD) 1
Visit 5: POD 3
Visit 6: POD 5
Visit 7 and 8: POD 7 or 14 (or day of discharge)
Visit 9: POD 30
Follow-up will be 3 months for safety endpoints.

Visite 2: einen Tag vor der Operation
Visite 3: am Operationstag
Visite 4: post-operativer Tag (POD) 1
Visite 5: POD 3
Visite 6: POD 5
Visite 7 und 8: POD 7 or 14 (oder Entlasstag)
Visite 9: POD 30
Follow-up 3 Monate

E.5.2

Secondary end point(s)

Feasibility endpoints:
•Adherence to study medication
•Completion of adjuvant chemotherapy
Oncologic endpoints:
•Overall survival
•Disease-free survival
•Rates of local / distant recurrence
Biological endpoints/Biomarkers (will be measured at different
timepoints of study conduct):
•Blood samples: c-reactive protein (CRP), albumin, differential
blood count, CA 19-9, carcinoembryonic antigen (CEA), cytokine
multiplex, PGE-2 levels, circulating tumor cells, RNA sequencing
in periphery blood cells (leukocytes)
•Tissue samples: COX-2 expression, PGE-2 levels, immune cell
infiltrate (immunehistochemistry), RNA sequencing of bulk tissue
or of sorted tumor and stromal cells.

Endpunkte Durchführbarkeit:
• Einhaltung der Studienmedikation
• Vollständigkeit der adjuvanten Chemotherapie
Onkologische Endpunkte:
• Gesamtüberlebensrate
• Krankheitsfreies Überleben
• Rezidivraten (lokal und entfernt)
Biologische Endpunkte/Biomarker:
• Blutproben: C-reaktives Protein (CRP), Albumin, Differentialblutbild, CA 19-9, karzinoembryonales Antigen, Multiplex Cytokin, PGE-2 Werte, zirkulierende Tumorzellen, RNA-Sequenzierung von peripheren Blutzellen (Leukozyten)
• Gewebeproben: COX-2 Expression, PGE-2 Werte, Infiltrate von Immunzellen, RNA-Sequenzierung von Gesamtgewebe oder sortierten Tumorzellen und Stromazellen.

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit 1: screening
Visit 2: one day before Operation
Visit 3: day of surgery
Visit 4: post-operative day (POD) 1
Visit 5: POD 3
Visit 6: POD 5
Visit 7 and 8: POD 7 or 14 (or day of discharge)
Visit 9: POD 30
Visit 10: POD 3 months
Visit 11: POD 6 months
Visit 12: POD 12 months
Visit 13: POD 24 months

Visite 1: Screening
Visite 2: einen Tag vor der Operation
Visite 3: am Operationstag
Visite 4: post-operativer Tag (POD) 1
Visite 5: POD 3
Visite 6: POD 5
Visite 7 und 8: POD 7 or 14 (oder Entlasstag)
Visite 9: POD 30
Visite 10: POD 3 Monate
Visite 11: POD 6 Monate
Visite 12: POD 12 Monate
Visite 13: POD 24 Monate
Follow-up 3 Monate

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Feasibility

Machbarkeit

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

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

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

last visit last subject (LVLS)

letzte Visite des letzten Patienten

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:

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

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. It is not different from the expected normal treatment of that condition.

Keine. Die Behandlung weicht nicht von der normalen Weiterbehandlung dieser Erkrankung ab.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Study Center of the German Surgical Society
G.4.3.4	Network Country	Germany
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Coordination Centre of Clinical Trials (KKS)
G.4.3.4	Network Country	Germany

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-06-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2021-07-09

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