Clinical Trials Register

Summary
EudraCT Number:	2019-002461-35
Sponsor's Protocol Code Number:	PREBOTPilot
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:	2019-07-17
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

2019-002461-35

A.3

Full title of the trial

Monocenter, randomized, controlled, open-label, phase-II clinical trial of PREoperative endoscopic injection of BOTulinum toxin in the sphincter of Oddi to reduce postoperative pancreatic fistula after distal pancreatectomy (PREBOTPilot)

Monozentrische, randomisierte, kontrollierte, offene, klinische Studie der Phase II zur Reduktion der postoperativen Pankreasfistel nach Pankreaslinksresektion durch eine präoperative endoskopische Injektion von Botulinumtoxin in den Sphinkter Oddi (PREBOTPilot)

A.3.1

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

Clinical trial investigating an endoscopic procedure with the aim to reduce the most frequent and potentially life-threatening complication in patients undergoing resection of the body and/or tail of the pancreas

Klinische Studie zur Reduktion der häufigsten und potentiell lebensbedrohlichen Komplikation nach Entfernung des Körpers und/oder Schwanzes der Bauchspeicheldrüse durch ein endoskopisches Verfahren

A.4.1

Sponsor's protocol code number

PREBOTPilot

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	Ruprecht-Karls-University Heidelberg Medical Faculty represented by Universitätsklinikum Heidelberg and its acting Comm
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	Federal Ministry of Education and Research
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	University Hospital Heidelberg, Department of General, Visceral, and Transplantation Surgery
B.5.2	Functional name of contact point	Clinical Project Management
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 110
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	+4962215634240
B.5.5	Fax number	+4962215633815
B.5.6	E-mail	claudia.mack@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	BOTOX
D.2.1.1.2	Name of the Marketing Authorisation holder	Allergan Pharmaceuticals Ireland
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Powder for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	93384-43-1
D.3.9.3	Other descriptive name	BOTULINUM TOXIN TYPE A
D.3.9.4	EV Substance Code	SUB13117MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

Elective distal pancreatectomy for any underlying disease

Geplante Pankreaslinksresektion zur operativen Behandlung
unterschiedlicher Bauchspeicheldrüsenerkrankungen

E.1.1.1

Medical condition in easily understood language

Elective resection of the body and/or tail of the pancreas for any
underlying disease

Geplante Entfernung des Körpers und/oder Schwanzes der
Bauchspeicheldrüse zur operativen Behandlung unterschiedlicher
Bauchspeicheldrüsenerkrankungen

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10013476
E.1.2	Term	Distal pancreatectomy
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 purpose of this study is to evaluate the safety and feasibilty of a preoperative endoscopic injection of botulinum toxin into the sphincter of Oddi within 3-10 days before distal pancreatectomy to reduce clinically relevant pancreatic fistula (POPF) and/or death, and to gain preliminary efficacy data which will serve as a basis for a subsequent confirmatory trial. The primary endpoint is the occurrence of clinically relevant POPF and/or death due to any cause within 30 days after surgery. Clinically relevant POPF is defined as grade B and C fistulas according to the currently updated definition of the International Study Group of Pancreatic Surgery (ISGPS). Safety is evaluated by the assessment of adverse events (AE) and serious adverse events (SAE).

In der vorliegenden Studie sollen primär die Sicherheit und Machbarkeit einer präoperativen Injektion von Botulinumtoxin in den Sphinkter Oddi innerhalb von 3-10 Tagen vor Pankreaslinksresektion untersucht werden, sowie erste randomisierte Daten zur Wirksamkeit der Studienintervention gewonnen werden. Primärer Endpunkt in Bezug auf die Wirksamkeit der Studienintervention ist das Auftreten einer klinisch relevanten Pankreasfistel (POPF Schweregrade B und C nach Konsensusdefinition der International Study Group of Pancreatic Surgery (ISGPS)) und/oder Tod innerhalb von 30 Tagen nach Pankreaslinksresektion. Die Sicherheit der Patienten wird durch Erfassung von Unerwünschten Ereignissen (Adverse Events, AE) und Schwerwiegenden Unerwünschten Ereignissen (Serious Adverse Events, SAE) überwacht.

E.2.2

Secondary objectives of the trial

The secondary objectives are to evaluate postinterventional and postoperative complications in intervention and control groups, i.e. the overall occurrence and severity of postoperative pancreatic Fistula (POPF) according to the International Study Group of Pancreatic Surgery (ISGPS), postinterventional pancreatitis, perioperative sepsis, delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), intraabdominal fluid collection/abscess, lymphatic fistula/chylus ascites, wound infection, burst abdomen, reinterventions/-operations, and overall mortality. Furthermore, quality of life, durations of intensive care unit/intermediate care unit stay and total hospital stay, and readmission due to postoperative complications will be evaluated.

Sekundäres Ziel ist die Untersuchung von klinisch relevanten Komplikationen nach der Intervention bzw. Operation in der Interventions- und Kontrollgruppe. Dazu gehören die Gesamthäufigkeit und Häufigkeit der Schweregrade der postoperativen Pankreasfistel (POPF) nach Konsensusdefinition der International Study Group of Pancreatic Surgery (ISGPS), die postinterventionelle Pankreatitis, perioperative Sepsis, verzögerte Magenentleerung, Postpankreatektomieblutung, intraabdominelle Flüssigkeitskollektion/Abszess, Lymphfistel, Wundinfekt, Platzbauch, Reinterventionen/-operationen und Gesamtmortalität. Außerdem werden die Lebensqualität, die Dauer des Aufenthaltes auf der Intensivstation, die Gesamtaufenthaltsdauer im Krankenhaus und Wiederaufnahmen ins Krankenhaus aufgrund von postoperativen Komplikationen untersucht.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

– Patients scheduled for elective, primary DP (open or
minimally invasive technique)
– Male or female patients ≥18 years of age
– Ability of patient to understand character and individual
consequences of the clinical trial
– Written informed consent (available before enrollment)
– For women with childbearing potential, presence of negative
urine or blood pregnancy test, and adequate contraception
until 14 days after trial intervention

Patienten, die für eine primäre Pankreaslinksresektion geplant sind (offen oder minimal-invasiv)
– Männer oder Frauen ≥18 Jahre alt
– Fähigkeit des Patienten, Wesen und individuelle Konsequenzen der Studie zu verstehen
– Unterschriebene Einwilligungserklärung
– Bei gebärfähigen Frauen: Nachweis eines negativen Schwangerschaftstests in Urin oder Blut, und Bereitschaft zur adäquaten Kontrazeption bis einschließlich Tag 14 nach Studienintervention

E.4

Principal exclusion criteria

Serious cardiovascular disease (e.g. myocardial infarction in
the last 12 months, congestive heart failure NYHA III/IV,
unstable angina pectoris)
– Serious renal insufficiency, i.e. creatinine clearance <30
mL/min
– Liver cirrhosis of any Child-Pugh grade
– American Society of Anesthesiologists (ASA) score >III
– Hypersensitivity to any botulinum toxin preparation or to any
of the components in the formulation
– Neuromuscular disorder, e.g. peripheral motor neuropathic
disease, amyotrophic lateral sclerosis or neuromuscular
junction disorders (e.g. myasthenia gravis or Lambert-Eaton
syndrome), or any other neurological disorder with
associated increased risk for the patient undergoing
botulinum toxin injection
– Any condition in which duodenoscopy and/or the trial
intervention is not possible, e.g. for anatomical reasons, or
obsolete in the actual situation, e.g. in patients with acute
pancreatitis
– History of botulinum toxin application and either positive test
or missing test for neutralizing antibodies to botulinum toxin
– Understanding or language problems
– Inability to comply with study and/or follow-up procedures
– Pregnancy or lactation
– Concurrent participation in another interventional clinical trial
– Any condition or situation which could result in an undue risk
for the patient and/or influence outcome measures in the
opinion of the investigator

Schwere kardiovaskuläre Erkrankung (z.B. Herzinfarkt während der letzten 12 Monate, Herzinsuffizienz NYHA III/IV, instabile Angina pectoris)
– Niereninsuffizienz, d.h. Kreatinin-Clearance nach Cockroft-Gault <30 mL/min
– Leberzirrhose
– American Society of Anesthesiologists (ASA)-Score >III
– Überempfindlichkeit gegenüber Botulinumtoxin-Präparaten oder eines Bestandteils in der Formulierung
– Neuromuskuläre Erkrankung, z.B. Periphere Motoneuron-Erkrankung, Amyotrophe Lateralsklerose oder Störung der neuromuskulären Synapse (z.B. Myasthenia gravis oder Lambert-Eaton-Syndrom) oder andere neurologische Erkrankung, einhergehend mit einem erhöhten Risiko einer Botox-Injektion
– Zustand, aufgrund dessen eine Ösophagogastroduodenoskopie und/oder die Studienintervention nicht möglich oder zum gegenwärtigen Zeitpunkt obsolet ist, z.B. aus anatomischen Gründen oder bei Patienten mit akuter Pankreatitis
– Vorausgehende Behandlung mit einem Botulinumtoxin-Präparat und entweder positiver Test oder nicht vorhandener Test auf neutralisierende Antikörper gegen Botulinumtoxin
– Verständnis- oder Sprachprobleme
– Incompliance
– Schwangerschaft oder Stillzeit
– Gleichzeitige Teilnahme an einer anderen Interventionsstudie
– Jeglicher Zustand oder Situation, der/die nach Einschätzung des Prüfarztes mit einem erhöhten Risiko für den Patienten einhergeht und/oder die Studienergebnisse beeinflussen könnte

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the occurrence of clinically relevant POPF (grades B/C) according to the ISGPS and/or death within 30 days after distal pancreatectomy.

Der primäre Endpunkt setzt sich zusammen aus der Häufigkeit klinisch relevanter postoperativer Pankreasfisteln (POPF Grade B und C nach ISGPS) und/oder Tod aufgrund jeglicher Ursache innerhalb von 30 Tagen nach Pankreaslinksresektion.

E.5.1.1

Timepoint(s) of evaluation of this end point

The combined primary endpoint is assessed during study visits on postoperative day (POD) 0, POD 3, day of clinical discharge and POD 30.

Der kombinierte primäre Endpunkt wird durch Studienvisiten am Tag der Operation, am 3. postoperativen Tag, am Tag der Entlassung aus dem Krankenhaus und am 30. postoperativen Tag erfasst.

E.5.2

Secondary end point(s)

The secondary endpoints are the following:
- Overall POPF rate and severity of POPF (i.e. grades B and C, and also biochemical leakage) until POD 30 and within 3 months after the index operation defined according to the currently updated ISGPS definition
- Postinterventional pancreatitis
- Perioperative sepsis
- Delayed gastric emptying (DGE)
- Post-pancreatectomy hemorrhage (PPH)
- Intraabdominal fluid collection/abscess
- Lymphatic fistula/chylus ascites
- Wound infection
- Burst abdomen
- Reinterventions/-operations due to any cause
- Mortality
- Quality of life
- Intensive care unit (ICU)/intermediate care unit (IMC) stay
- Total hospital stay
- Readmission to hospital for management of postoperative complications
For each endpoint, a definition is given in the clinical trial protocol.

Die sekundären Endpunkte sind die folgenden:
- Gesamtrate an postoperativen Pankreasfisteln (POPF) und deren Schweregrade (d.h. Grade B und C und auch „biochemical leakage“ nach aktualisierter Konsensusdefinition der ISGPS
- Postinterventionelle Pankreatitis
- Perioperative Sepsis
- Verzögerte Magenentleerung
- Postpankreatektomieblutung
- Intraabdominelle Flüssigkeitskollektion/Abszess
- Lymphfistel
- Wundinfekt
- Platzbauch
- Reinterventionen/-Operationen
- Gesamtmortalität
- Lebensqualität
- Dauer des Aufenthaltes auf der Intensivstation
- Gesamtaufenthaltsdauer im Krankenhaus
- Wiederaufnahme ins Krankenhaus aufgrund von postoperativen Komplikationen
Jeder Endpunkt ist im Protokoll definiert.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints are assessed during study visits on postoperative day (POD) 3, day of discharge, POD 30 and 3 months after the index operation (distal pancreatectomy).

Die sekundären Endpunkte werden durch Studienvisiten am 3. postoperativen Tag, am Tag der Entlassung aus dem Krankenhaus, am 30. postoperativen Tag und 3 Monate nach der Indexoperation (Pankreaslinksresektion) erfasst.

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Keine präoperative Intervention

No preoperative intervention

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

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

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.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)

The treatment after the patient has ended the participation is not different from the expected normal treatment of the underlying disease.

Die Behandlung des Patienten nach Studienende entspricht der Standardbehandlung der zugrunde liegenden
Bauchspeicheldrüsenerkrankung.

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	Institute of Medical Biometry and Informatics (IMBI)
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 Center for 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

2019-12-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-07

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-10-11

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