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

Study Overview
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Brief Summary
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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
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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)

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

Conditions
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Distal Pancreatectomy, Postoperative Pancreatic Fistula

Intervention / Treatment
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* Drug: botulinum toxin injection


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: botulinum toxin injection<br>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. | Drug: botulinum toxin injection<br>* injection of Botulinum toxin A 100 UI, single dose administration, in the major papilla, in the Oddi sphincter, during upper gastrointestinal endoscopy.<br>|
| No Intervention: standard care<br>standard care (no endoscopy) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of postoperative pancreatic fistula | 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 | Grade of postoperative pancreatic fistulas B based on the ISGPF 2016 update | 3 months | 
| number of postoperative pancreatic fistulas grade C | Grade of postoperative pancreatic fistulas C based on the ISGPF 2016 update | 3 months | 
| Quantity of Biochemical leak after surgery | Biochemical leak after surgery | 3 months | 
| number of Postoperative complications | 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 | CLAVIEN-DINDO classification for post-surgical morbidity | 3 months | 
| Number of hospital days | Health economics endpoints : duration of hospital stay | 3 months | 
| Number of hospital readmissions | Health economics endpoints : hospital readmissions | 3 months | 
| Number of transfer to intensive care unit and the duration of these stays | Health economics endpoints : transfer to intensive care unit and the duration of these stays | 3 months | 
| Number of fistularelated postoperative invasive procedures | Health economics endpoints : fistularelated postoperative invasive procedures | 3 months | 
| overall costs of hospitalization | Health economics endpoints : overall costs | 3 months | 
| Quality of life EQ-5D-5L questionnaire | 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 | number of sides effects (complications) related to the endoscopic botulinum toxin injection | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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distal pancreatectomy