Examining the impact of propranolol on preoperative anxiety and on tumorigenic changes in patients with pancreatic ductal adenocarcinomas: a randomized, triple-blinded, placebo-controlled pilot trial (The IMPULS trial)

The study will be conducted as a pilot study to test efficacy, safety and feasibility of propranolol on preoperative anxiety in patients undergoing abdominal surgery for suspected pancreatic cancer. Furthermore, we will explore the implementation of the trial including compliance of the participants in a hybrid type 1 setup. A total of 30 participants will be included and randomized to receive either propranolol or placebo twice daily with 15 patients in each arm. Following this study, a power calculation will be done to reveal the actual number of needed participants in each arm for a potential follow-up randomized clinical trial on primary outcomes of interest. Thus, the results from this study can be used for future power calculations for clinical trials related to this topic.

Primary objectives: Efficacy Evaluating the efficacy of preoperative propranolol on patient-experienced anxiety and on tumorigenic gene expression compared to placebo is the primary objective of this trial. We further divide the primary objectives in to primary clinical objectives, primary translational objectives and exploratory endpoints.

Primary clinical objectives The primary clinical objectives are to evaluate preoperative patient-experienced anxiety in patients receiving the nonselective 2-adrenergic receptor inhibitor, propranolol, compared to placebo. Further, we will measure heart rate variability (HRV) in order to evaluate changes in the autonomous nervous system in relation to surgery. HRV is calculated from the interval variation between consecutive R waves in an ECG time series69,70, and results suggest that it is associated with the intra- and postoperative complications71. As HRV reflects sinoatrial node regulation, we expect it to be affected by the beta-adrenergic blockade caused by preoperative propranolol. Analyzing this relation will provide essential knowledge in understanding how HRV behaves perioperatively. Lastly, we will make a follow up on the participants receiving propranolol compared to placebo.

Primary translational objectives: The primary translational objectives are to examine the systemic (biochemical) and local changes (TME of resections) to propranolol treatment compared to placebo. Alterations in pro-metastatic and proinflammatory genes will specifically be analyzed.

Secondary objective: Safety The secondary objective is to assess tolerance and safety of the intervention in this pilot study (e.g., adverse effects, number of patients that need dose reduction etc.). We will evaluate changes in heart rate (HR) and blood pressure (BP) during the intervention period to test safety and tolerability of preoperative propranolol.

2.3.3 Tertiary objectives: Feasibility Additionally, we will examine the feasibility of this intervention using the APEASE framework72, which assesses factors like affordability, practicability, effectiveness, acceptability, side-effects, and equity, thereby determining the willingness to adopt this strategy. This will help identify barriers and enablers to a future larger study. The details regarding the APEASE framework are described under assessments.