Preventing Postoperative Complications in Patients Undergoing High-risk Pancreatoduodenectomy With a Bundle Approach Including Hydrocortisone, Octreotide, and the Teres Ligament Patch (PANENCA)

The PANENCA trial is an international, multicenter, randomized controlled superiority trial designed to evaluate whether a standardized perioperative bundle approach reduces major postoperative complications in patients undergoing pancreatoduodenectomy who are at high risk for postoperative pancreatic fistula (POPF). High risk is defined preoperatively by a small main pancreatic duct diameter (≤3 mm) on cross-sectional imaging, which is associated with soft pancreatic parenchyma and an increased risk of anastomotic failure. POPF remains the leading cause of morbidity and mortality following pancreatoduodenectomy. Several low-cost and widely available interventions have individually demonstrated effectiveness in reducing POPF or its sequelae; however, these measures have not been implemented consistently, systematically evaluated in a large international randomized trial, nor combined into a standardized perioperative strategy. The PANENCA trial therefore evaluates a bundled intervention (the HOP bundle) consisting of the following components: 1. Hydrocortisone, administered intravenously starting during induction of anesthesia to attenuate the postoperative inflammatory response, which is considered a key contributor to the development of POPF. Hydrocortisone is administered at a dose of 100 mg three times daily for three days, resulting in a total of 9 doses. 2. Octreotide, administered subcutaneously starting during induction of anesthesia, to reduce exocrine pancreatic secretion during the early postoperative period. Octreotide is administered at a dose of 0.1 mg three times daily for up to seven days or until earlier discharge, with a maximum of 21 doses. 3. A ligamentum teres hepatis patch, applied intraoperatively to mechanically protect the gastroduodenal artery stump from enzymatic erosion in the event of a POPF. The ligamentum teres is positioned between the gastroduodenal artery stump and the pancreatojejunostomy, functioning as an interpositional layer or wrap around one or both structures. These interventions have potential complementary and non-overlapping mechanisms of action and are supported by prior randomized trials and meta-analyses. All investigational medicinal products are authorized and are used within approved or evidence-based indications. Eligible patients are randomized in a 1:1 ratio prior to surgery to receive either the HOP bundle in addition to standard perioperative care or standard perioperative care alone. Randomization is stratified by participating center to account for potential inter-center variability. The trial is classified as a low-interventional clinical trial according to the European Union Clinical Trials Regulation (EU No 536/2014), as it uses authorized medicinal products, evidence-based dosing regimens, and does not require additional diagnostic or monitoring procedures beyond standard clinical practice. Patients are followed from the day of surgery until hospital discharge, with additional follow-up to 90 days postoperatively for assessment of postoperative complications, readmissions, and mortality. No additional outpatient visits or diagnostic procedures are mandated beyond routine postoperative care. The trial is powered to detect a superiority effect of the HOP bundle on the primary endpoint of major postoperative complications. Sample size calculations are based on contemporary national audit data demonstrating a substantially higher complication rate in patients with small pancreatic ducts. Allowances are made for intraoperative non-resection due to metastatic disease and for minimal loss to follow-up. A predefined interim analysis for futility and safety is planned. Detailed statistical methodology, including handling of missing data and definition of analysis populations, is specified in the statistical analysis section of the protocol. Data are collected prospectively using a standardized electronic case report form (eCRF). Variables collected include baseline characteristics, intraoperative details, postoperative outcomes, and adverse events, all of which are routinely recorded as part of standard surgical care. Definitions of postoperative complications follow internationally accepted criteria, including those of the International Study Group of Pancreatic Surgery (ISGPS). Data quality is ensured through predefined range and consistency checks within the eCRF system, central data monitoring, and on-site or remote monitoring in accordance with Good Clinical Practice (GCP). Source data verification is performed on a risk-based basis by comparison with medical records and operative reports. Serious adverse events and suspected unexpected serious adverse reactions are reported in accordance with regulatory requirements and overseen by an independent Data Safety Monitoring Board. Both hydrocortisone and octreotide have well-established safety profiles. Given the short duration and low dosing used in this trial, the additional risk to participants is considered minimal. Postoperative monitoring, including glucose monitoring and routine laboratory assessments, follows standard clinical practice. Criteria for temporary trial suspension or early termination are predefined, and safety oversight is provided by an independent monitoring committee. The study is conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation Good Clinical Practice (ICH-GCP), and applicable national and European regulations. Written informed consent is obtained from all participants prior to enrollment. Patient representatives were involved in the design of the trial and will remain engaged throughout its conduct and dissemination of results. Upon completion, study results will be submitted for publication in peer-reviewed journals and presented at international scientific meetings. A summary of results will be made publicly available in accordance with applicable transparency regulations.