Clinical trial NCT04220931: Intrapapillary Botulinum Toxin Injection for PREvention of Post-surgical PAncREactic Fistula
Official title: Intrapapillary Botulinum Toxin Injection for PREvention of Post-surgical PAncREactic Fistula
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Distal Pancreatectomy
Postoperative Pancreatic Fistula
Keywords: distal pancreatectomy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-01-07
Enrollment: 460
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)

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)

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

Primary outcomes:
measure: number of postoperative pancreatic fistula
timeFrame: 3 months
Secondary outcomes:
measure: number of postoperative pancreatic fistulas grade B
timeFrame: 3 months
measure: number of postoperative pancreatic fistulas grade C
timeFrame: 3 months
measure: Quantity of Biochemical leak after surgery
timeFrame: 3 months
measure: number of Postoperative complications
timeFrame: 3 months
measure: CLAVIEN-DINDO classification for post-surgical morbidity
timeFrame: 3 months
measure: Number of hospital days
timeFrame: 3 months
measure: Number of hospital readmissions
timeFrame: 3 months
measure: Number of transfer to intensive care unit and the duration of these stays
timeFrame: 3 months
measure: Number of fistularelated postoperative invasive procedures
timeFrame: 3 months
measure: overall costs of hospitalization
timeFrame: 3 months
measure: Quality of life EQ-5D-5L questionnaire
timeFrame: 3 months
measure: Number of sides effects (complications) related to the endoscopic botulinum toxin injection
timeFrame: 3 months
Other outcomes:
Locations:
city: Clichy
country: France
facility: PRAT
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Frederic Prat, prof
role: PRINCIPAL_INVESTIGATOR
References: