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

NCT ID: NCT04220931

Last Updated: 2023-07-10

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 460 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-27
• Study Completion Date: 2027-03-01

Brief Summary

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

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)

Conditions

Distal Pancreatectomy; Postoperative Pancreatic Fistula

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

botulinum toxin injection

Intervention Type: DRUG

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

standard care

standard care (no endoscopy)

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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.

Intervention Type: DRUG

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Frederic Prat, prof

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

PRAT

Clichy, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Frederic Prat, Prof

Role: CONTACT

frederic.prat@aphp.fr

0033(1)40875663

Alain Sauvanet, Prof

Role: CONTACT

alain.sauvanet@aphp.fr

Facility Contacts

Frederic Prat, pr

Role: primary

frederic.prat@aphp.fr

Other Identifiers

P170913J

Identifier Type: -

Identifier Source: org_study_id