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The IMPULS trial is a randomized, triple-blinded, placebo controlled, single center, pilot trial examining the efficacy and safety of preoperative propranolol in patients scheduled for pancreatic cancer surgery. The study is conducted as a type 1 hybrid efficacy-implementation trial of 30 patients.
This study is designed to provide pilot data for a future larger perioperative study of propranolol with the aim of improving outcomes for pancreatic cancer surgery.
In total, 30 participants will be allocated in a 1:1 ratio with 15 participants enrolled in each trial arm (propranolol vs. placebo). Participants will be allocated to either 40 mg propranolol twice daily or placebo twice daily in 10 days prior to planned surgery.
Primary outcomes: Evaluating the efficacy of preoperative propranolol on anxiety and in pro-tumorigenic changes (e.g., in the tumor tissue and in blood samples) in patients undergoing surgery for pancreatic cancer. Furthermore, to obtain follow up data (e.g., 90-day mortality, postoperative complications etc. on the patients receiving propranolol versus placebo). Heart rate variability among the participants will also be examined.
Secondary: Examining the safety and tolerability of 40 mg preoperative propranolol twice daily in patients undergoing surgery for pancreatic cancer.
Tertiary: Evaluating the feasibility and implementation of the trial (using the APEASE framework). This will help identify barriers and enablers to a future larger study.
Short-time propranolol treatment is considered safe with a mild and manageable safety-profile. Risk-management, mitigations and guidelines to ensure patient safety is included in the protocol. Since this clinical trial is exploratory in nature, no sample-size calculation is performed.
Full description
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 ductal adenocarcinoma (PDAC). Furthermore, the implementation of the trial including compliance of the participants in a hybrid type 1 setup will be examined.
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.
Primary objectives are further divided 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 beta-2-adrenergic receptor inhibitor, propranolol, compared to placebo.
Further, heart rate variability (HRV) will be measured 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 series and results suggest that it is associated with the intra- and postoperative complications. As HRV reflects sinoatrial node regulation, it is expected 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, follow up on the participants receiving propranolol compared to placebo will be done.
Primary clinical effect parameters:
The following primary effect parameters will be used to investigate the primary clinical objectives:
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.
Primary translational effect parameters:
Exploratory endpoints:
The potential influence of inter-participant genetic variations (pharmacogenetics) on measured levels of serum propranolol and response to surgical stress will be investigated as exploratory endpoints. The differences in drug metabolism (pharmacokinetics) among participants will also be of interest.
Secondary objectives: Safety
Secondarily, tolerance and safety of the intervention in this pilot study (e.g., adverse effects, number of patients that need dose reduction etc.) will be evaluated. Changes in heart rate (HR) and blood pressure (BP) during the intervention period will be examined to test safety and tolerability of preoperative propranolol.
Secondary effect parameters:
Tertiary objectives: Feasibility
Additionally, the feasibility of this intervention using the APEASE framework, which assesses factors like affordability, practicability, effectiveness, acceptability, side-effects, and equity, thereby determining the willingness to adopt this strategy will be examined. This will help identify barriers and enablers to a future larger study. The details regarding the APEASE framework are described under assessments.
This trial will be conducted in accordance with the principles of Good Clinical Practice and reported according to the CONSORT and the complimentary StaRI standards for implementation studies.
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Inclusion criteria
Women of childbearing potential (WOCBP) are defined as women ranging from the period of menarche till the post-menopausal period, unless permanently sterile (e.g., hysterectomy, bilateral salpingectomy and bilateral oophorectomy). Post-menopause is defined as no menses for 12 months without an alternative medical cause.
WOCBP should use a secure and highly effective birth control (as stated in the "Recommendations related to contraception and pregnancy testing in clinical trials", version 1.1., section 4.1, from the Clinical Trials Facilitation and Coordination Group) during the entire period of the trial. In cases of uncertainty regarding pregnancy, additional pregnancy testing either as highly sensitive serum or urine pregnancy test can be used.
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30 participants in 2 patient groups, including a placebo group
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Central trial contact
Ismail Gögenur, Professor; Adile Orhan, MD
Data sourced from clinicaltrials.gov
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