Intrapapillary Botulinum Toxin Injection for PREvention of Post-surgical PAncREactic Fistula (PREPARE)

Surgery is required for the treatment of many pancreatic conditions, either malignant or benign. Mortality of pancreatic surgery can be up to 3% even in expert centers. Morbidity is high, postoperative pancreatic fistula (POPF) being the main postoperative complication. In its current definition (drain output of any measurable fluid >= postoperative day 3 with amylase content >3 times the serum amylase activity and with clinical consequence), the incidence of postoperative PF is between 15 and 30 %. Most POPF resolve spontaneously but when refractory POPF occurs, it may lead to severe complications. POPF severity is graded as follows: grade B in case of change in medical management: infection without organ failure, specific medication (total parenteral nutrition, somatostatin analogs, antibiotics), persistent drainage > 3 weeks, angiographic procedure for bleeding, prolonged hospital stay; grade C in case of reoperation or PF-related organ failure or death.

No specific prophylactic treatment of POPF is currently recommended by clinical guidelines. In clinical research, many prophylactic strategies have been attempted with partial efficacy. Endoscopic pancreatic sphincterotomy with plastic stent placement is effective in pre-and postoperative management of pancreatic fistula but with the need of a highly competent interventional endoscopist. Intrapapillary botulinum toxin injection is believed to induce relaxation of the pancreatic sphincter, leading to a " pharmacological " pancreatic sphincterotomy without any morbidity.

A recent phase I/II prospective study has shown promising results in this indication, with no clinically relevant pancreatic fistula when botulinum toxin was injected. Based on this observation we hypothesize that intrapapillary botulinum toxin injection during an endoscopic procedure before surgery could be effective for the prevention of post-surgical pancreatic fistula

Study Overview

Detailed Description

Surgery is required for the treatment of many pancreatic conditions, either malignant or benign. Mortality of pancreatic surgery can be up to 3% even in expert centers. Morbidity is high, postoperative pancreatic fistula (POPF) being the main postoperative complication. In its current definition (drain output of any measurable fluid >= postoperative day 3 with amylase content >3 times the serum amylase activity and with clinical consequence), the incidence of postoperative PF is between 15 and 30 %. Most POPF resolve spontaneously but when refractory POPF occurs, it may lead to severe complications. POPF severity is graded as follows: grade B in case of change in medical management: infection without organ failure, specific medication (total parenteral nutrition, somatostatin analogs, antibiotics), persistent drainage > 3 weeks, angiographic procedure for bleeding, prolonged hospital stay; grade C in case of reoperation or PF-related organ failure or death.

No specific prophylactic treatment of POPF is currently recommended by clinical guidelines. In clinical research, many prophylactic strategies have been attempted with partial efficacy. Endoscopic pancreatic sphincterotomy with plastic stent placement is effective in pre-and postoperative management of pancreatic fistula but with the need of a highly competent interventional endoscopist. Intrapapillary botulinum toxin injection is believed to induce relaxation of the pancreatic sphincter, leading to a " pharmacological " pancreatic sphincterotomy without any morbidity.

A recent phase I/II prospective study has shown promising results in this indication, with no clinically relevant pancreatic fistula when botulinum toxin was injected. Based on this observation we hypothesize that intrapapillary botulinum toxin injection during an endoscopic procedure before surgery could be effective for the prevention of post-surgical pancreatic fistula

This study will be a prospective, multicentric, phase III, superiority, controlled, randomized (1:1), open-label, clinical trial with two parallel arms (intrapapillary botulinum toxin versus standard care), using a PROBE (Prospective Randomized Open Blinded End-point) methodology.

Patients with scheduled distal pancreatectomy for any indication

Sources of funding for the trial : French Ministry supports this study by PHRC-N 2017.

The botulinum toxin provides by MERZ France (producer of Xeomin)

Study Type

Interventional

Enrollment (Estimated)

460

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients with scheduled distal pancreatectomy for any indication: open or laparoscopic distal pancreatectomy with or without splenectomy
  • Age ≥ 18years

Exclusion Criteria:

  • History of myasthenia gravis or Eaton-Lambert syndrome
  • Inflammatory myositis <2 years or preexisting motor neuron disease or neuropathies
  • ASA score > III
  • Pregnancy or lactation
  • Altered anatomy of the duodenum and/or the major papilla (prior surgery, prior endoscopic sphincterotomy)
  • Scheduled pancreaticoduodenectomy (Whipple procedure)
  • Scheduled total pancreatectomy
  • Scheduled central pancreatectomy
  • Scheduled pancreatic enucleation
  • Calcified chronic pancreatitis (suspected on preoperative cross-sectional imaging)
  • Pancreas divisum (suspected on preoperative cross-sectional imaging)
  • Toxin botulinum contraindications (hypersensitivity to albumin or to saccharose, infection or inflammation at the injection site concerned, generalized muscle weakness)
  • Preoperative administration of somatostatin analogs: for long-acting somatostatin analogs, a 1-month washout period is necessary; for short-acting somatostatin analogs, a 24-hours washout period is necessary
  • Any kind of surgical method to reinforce the pancreatic stump:
  • Use of a bioabsorbable patch
  • Use of fibrin glue
  • Use of a ligament patch
  • Tutorship, trusteeship
  • Concurrent participation in other experimental trials
  • Not Affiliation to the French social security
  • Not Ability to give their consent and not written informed consent
  • Distal pancreatectomy extended to neighbouring organs (except spleen and gallbladder) or to the vessels (celiac axis, portal vein)

Secondary exclusion criteria: patients who did not have the planned surgery in less than 4 weeks after the botulinum toxin injection.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: botulinum toxin injection

Injection of Botulinum toxin A 100 UI, single dose administration, in the major papilla, in the Oddi sphincter, during upper gastrointestinal endoscopy.

The endoscopic procedure will be performed under unconscious sedation with intravenous injection of propofol by an anesthesiologist.

injection of Botulinum toxin A 100 UI, single dose administration, in the major papilla, in the Oddi sphincter, during upper gastrointestinal endoscopy.
No Intervention: standard care
standard care (no endoscopy)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
number of postoperative pancreatic fistula
Time Frame: 3 months
Clinically relevant POPF (grade B and C) in the 3 months after Distal Pancreatectomy
3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
number of postoperative pancreatic fistulas grade B
Time Frame: 3 months
Grade of postoperative pancreatic fistulas B based on the ISGPF 2016 update
3 months
number of postoperative pancreatic fistulas grade C
Time Frame: 3 months
Grade of postoperative pancreatic fistulas C based on the ISGPF 2016 update
3 months
Quantity of Biochemical leak after surgery
Time Frame: 3 months
Biochemical leak after surgery
3 months
number of Postoperative complications
Time Frame: 3 months

Postoperative complications :

  • intra-abdominal fluid collection
  • delayed gastric emptying
  • hemorrhage
  • pancreatitis
  • wound infection
  • other infectious complication
3 months
CLAVIEN-DINDO classification for post-surgical morbidity
Time Frame: 3 months
CLAVIEN-DINDO classification for post-surgical morbidity
3 months
Number of hospital days
Time Frame: 3 months
Health economics endpoints : duration of hospital stay
3 months
Number of hospital readmissions
Time Frame: 3 months
Health economics endpoints : hospital readmissions
3 months
Number of transfer to intensive care unit and the duration of these stays
Time Frame: 3 months
Health economics endpoints : transfer to intensive care unit and the duration of these stays
3 months
Number of fistularelated postoperative invasive procedures
Time Frame: 3 months
Health economics endpoints : fistularelated postoperative invasive procedures
3 months
overall costs of hospitalization
Time Frame: 3 months
Health economics endpoints : overall costs
3 months
Quality of life EQ-5D-5L questionnaire
Time Frame: 3 months
The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state : LEVEL 1: indicating no problem LEVEL 2: indicating slight problems LEVEL 3: indicating moderate problems LEVEL 4: indicating severe problems LEVEL 5: indicating unable to/extreme problems
3 months
Number of sides effects (complications) related to the endoscopic botulinum toxin injection
Time Frame: 3 months
number of sides effects (complications) related to the endoscopic botulinum toxin injection
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Frederic Prat, prof, Assistance Publique - Hôpitaux de Paris

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 27, 2023

Primary Completion (Estimated)

December 31, 2026

Study Completion (Estimated)

March 1, 2027

Study Registration Dates

First Submitted

December 20, 2019

First Submitted That Met QC Criteria

January 6, 2020

First Posted (Actual)

January 7, 2020

Study Record Updates

Last Update Posted (Actual)

July 10, 2023

Last Update Submitted That Met QC Criteria

July 7, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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