Evaluation of Propranolol on Preoperative Anxiety and Tumorigenic Gene Expression in Pancreatic Ductal Adenocarcinoma: A Randomized, Triple-Blinded, Placebo-Controlled Pilot Study

The primary objective of this study is to evaluate the **efficacy** of preoperative **propranolol** on patient-experienced anxiety and tumorigenic gene expression in individuals undergoing abdominal surgery for suspected pancreatic ductal adenocarcinoma. This involves assessing the impact of propranolol, a nonselective β2-adrenergic receptor inhibitor, compared to placebo on preoperative anxiety levels and heart rate variability (HRV), which reflects changes in the autonomous nervous system and is associated with intra- and postoperative complications. Additionally, the study aims to analyze systemic and local biochemical changes, specifically alterations in pro-metastatic and proinflammatory genes, due to propranolol treatment.

The secondary objective focuses on the **safety** and tolerability of propranolol, assessing adverse effects, dose reductions, and changes in heart rate and blood pressure during the intervention period. This pilot study will provide essential data for future power calculations and the design of larger clinical trials on this topic.

The clinical trial involves a total of 30 participants, equally divided into two groups, with 15 individuals in each arm receiving either **propranolol** or a placebo. The study population comprises both male and female adults, with an age range starting from 18 years and above. Participants are selected based on their diagnosis of suspected surgically resectable pancreatic ductal adenocarcinoma (PDAC) and must be eligible for surgical treatment with curative intent. All participants are required to provide written informed consent. The trial does not include any vulnerable populations. The sponsor has not provided specific information regarding the general health status, lifestyle considerations, or habits of the participants. The study aims to evaluate the efficacy, safety, and feasibility of propranolol in managing preoperative anxiety in patients undergoing abdominal surgery for suspected pancreatic cancer.

The clinical trial is designed as a **randomized**, triple-blinded, placebo-controlled pilot study to evaluate the efficacy, safety, and feasibility of **propranolol** in patients with suspected surgically resectable pancreatic ductal adenocarcinoma. The trial will involve 30 participants who will be randomly assigned to receive either propranolol or a placebo, administered orally twice daily, with 15 patients in each arm. The study aims to assess the impact of propranolol on preoperative anxiety and tumorigenic changes, with primary endpoints including anxiety levels measured by The Hamilton Anxiety Rating Scale (HAM-A) and The Hospital Anxiety and Depression Scale (HADS), as well as heart rate variability (HRV) data collected via Holter monitor. Secondary endpoints focus on safety, monitoring changes in heart rate and blood pressure, and documenting any adverse effects such as light-headedness or hypotension.

The trial is expected to commence recruitment on December 1, 2023, and conclude by December 31, 2026. Participants will be involved in the study for a maximum treatment period of two weeks. The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor treatment effects and collect data on primary and secondary endpoints. The end-of-study visit will involve a comprehensive assessment of the participant's condition and any long-term effects of the treatment. Participants may be withdrawn from the study if they experience significant adverse effects or if they are unable to comply with the study protocol.

Inclusion criteria require participants to be at least 18 years old, with a clinical indication for surgical treatment of pancreatic cancer and the ability to provide written informed consent. The study will not include any specific exclusion criteria. The trial's findings will contribute to future power calculations for larger clinical trials, potentially leading to improved management strategies for patients with pancreatic ductal adenocarcinoma. The study will also explore the feasibility of the intervention using the APEASE framework, assessing factors such as affordability and acceptability to inform the design of subsequent studies.

The clinical trial involves the administration of **propranolol**, a nonselective β2-adrenergic receptor inhibitor, as the experimental medication. **Propranolol** is provided in the form of a tablet and is administered orally. The dosage regimen includes a maximum daily dose of 80 mg, with a total maximum dose of 1120 mg over the treatment period. The treatment duration is set for a maximum of 2 weeks. The primary objective of using **propranolol** in this trial is to evaluate its efficacy in reducing preoperative anxiety and its impact on tumorigenic gene expression in patients with pancreatic ductal adenocarcinomas. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.

The study also includes a **placebo** group to serve as a comparator. The **placebo** is formulated as a tablet, identical in appearance to the **propranolol** tablet, and is administered orally. The **placebo** contains lactose monohydrate and a gelatine capsule of bovine origin, with no active pharmacological ingredients. Participants in the **placebo** group receive the same administration schedule as those in the **propranolol** group, with a maximum treatment period of 2 weeks. The inclusion of a **placebo** group allows for a controlled comparison to assess the true effects of **propranolol** on the study's primary and secondary objectives.

The efficacy of propranolol in reducing preoperative anxiety and affecting tumorigenic changes in patients with suspected pancreatic cancer will be assessed through a randomized, triple-blinded, placebo-controlled pilot trial. The primary endpoints for evaluating efficacy include anxiety levels measured by The Hamilton Anxiety Rating Scale (HAM-A) and The Hospital Anxiety and Depression Scale (HADS). Additionally, the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire for pancreatic cancer will be utilized to assess quality of life. Heart rate variability (HRV) data will be calculated from continuous ECG gathered by a Holter monitor to evaluate changes in the autonomous nervous system. Follow-up data will include postoperative complications and survival rates at 30, 90 days, and 1, 3, and 5 years post-surgery. Blood and tissue samples will also be collected for analysis.

The trial will involve 30 participants, randomized to receive either propranolol or placebo twice daily, with 15 patients in each arm. The primary clinical objectives focus on evaluating preoperative patient-experienced anxiety and HRV changes due to the beta-adrenergic blockade caused by propranolol. The primary translational objectives aim to examine systemic and local changes in pro-metastatic and proinflammatory gene expression due to propranolol treatment compared to placebo. The secondary objective is to assess the safety and tolerability of propranolol by monitoring changes in heart rate and blood pressure, as well as recording any adverse effects such as light-headedness, lethargy, hypotension, and bradycardia.