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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Circulating tumor cells before and after intervention in blood samples.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with suspected surgically resectable pancreatic cancer
- •Indication for surgical treatment with curative intend.
- •Provide written informed consent.
- •Patients minimum 18 years old.
- •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.
排除标准
- •Patients with:
- •Chronic hypotension, systolic blood pressure < 100 mg Hg for women and < 110 mg Hg for men.
- •Bradycardia, pulse < 50 beats per minute.
- •Asthma or chronic obstructive lung disease
- •Heart insufficiency with affected (< 50 %) left ventricle ejection fraction (LVEF), treated or untreated.
- •Kidney insufficiency, defined as eGFR < 20 ml/min.
- •Liver insufficiency defined as chronically high liver enzymes or known chronic liver disease (e.g., hepatitis, steatosis, cirrhosis).
- •Cor pulmonale
- •Cardiogenic shock
- •Severe peripheral circulatory disorders
- •Known or newly diagnosed current metabolic acidosis (e.g., in recent analysis of arterial puncture).
- •Known hypersensitivity to propranolol or to one or more of the excipients.
- •Currently untreated pheochromocytoma.
- •History of Prinzmetals angina.
- •History of sick sinus syndrome or atrioventricular block.
- •History of stroke or any previous cardiovascular event.
- •History of neoadjuvant oncological treatment for suspected primary pancreatic cancer.
- •Recent or present (within 3 months) use of propranolol or any other beta-blocker.
- •Recent or present (within 3 months) use of any of the following medications: anxiolytics, calcium channel blockers, beta-adrenergic receptor agonist.
- •Medical history that classifies the patient as frail or unsuitable for inclusion by the examining physician.
- •Histopathological examination revealing benign lesion.
- •Predictable poor compliance, due to pre-existing psychiatric disease, dementia or not able to read or speak sufficient Danish, resulting in not being able to provide a well-informed written consent.
研究组 & 干预措施
Propranolol
Propranolol will be administered 40 mg twice daily (morning and evening) in 10 days prior to surgery for pancreatic cancer
干预措施: Propranolol (Drug)
Placebo
Placebo will be administered twice daily (morning and evening) in 10 days prior to surgery for pancreatic cancer.
干预措施: Placebo (Drug)
结局指标
主要结局
Circulating tumor cells before and after intervention in blood samples.
时间窗: Through study completion. At latest within 1 year from last participant completes trial.
Assessment of circulating tumor cells in blood samples before and after intervention.
Density and subtypes of tumor-infiltrating lymphocytes in the tumor microenvironment.
时间窗: Through study completion. At latest within 1 year from last participant completes trial.
Histopathological assessment of the density and subtypes of tumor-infiltrating lymphocytes. Immunohistochemistry technique will be used.
Neural markers in the tumor microenvironment.
时间窗: Through study completion. At latest within 1 year from last participant completes trial.
Histopathological assessment of neural marker expression (e.g., NGF, BDNF, tyrosin hydroxylase) Immunohistochemistry technique will be used.
Preoperative anxiety
时间窗: Obtained preoperatively at baseline (immediately after inclusion) and immediately after intervention (before surgery)
Assessed through the Hamilton Anxiety Rating Scale (HAMA) questionnaire
Preoperative anxiety and depression
时间窗: Obtained preoperatively at baseline (immediately after inclusion) and immediately after intervention (before surgery)
Assessed through the Hospital Anxiety and Depression Scale (HADS) questionnaire
Adrenergic receptor (ADRB1&ADRB2) expression in the tumor microenvironment.
时间窗: Through study completion. At latest within 1 year from last participant completes trial.
Histopathological assessment of the expression of adrenergic receptors (ADRB1 and ADRB2). Immunohistochemistry technique will be used for this purpose.
Survival 30-days after surgery
时间窗: After participant finishes trial and when last follow up (5 years from surgery) date is due.
Assessment of survival 30 days after surgery.
Overall survival 5-years after surgery
时间窗: After participant finishes trial and when last follow up (5 years from surgery) date is due.
Assessment of overall survival 5-years after surgery
Preoperative quality of life
时间窗: Obtained preoperatively at baseline (immediately after inclusion) and immediately after intervention (before surgery)
Preoperative quality of life assessed through the quality of life questionnaire.
Desmoplasia in the tumor microenvironment.
时间窗: Through study completion. At latest within 1 year from last participant completes trial.
Histopathological assessment of desmoplasia in the tumor microenvironment. Immunohistochemistry technique will be used.
Heart rate variability in both trial arms
时间窗: Through study completion, an average of 1 year.
Examining differences in heart rate variability among participants and between intervention and comparator group.
Overall survival 1-year after surgery
时间窗: After participant finishes trial and when last follow up (5 years from surgery) date is due.
Assessment of overall surival 1-year after surgery
Overall survival 3-years after surgery
时间窗: After participant finishes trial and when last follow up (5 years from surgery) date is due.
Assessment of overall survival 3-years after surgery
Spatial distribution of immune cells in the tumor microenvironment.
时间窗: Through study completion. At latest within 1 year from last participant completes trial.
Spatial distribution of immune cells in the tumor microenvironment using Immunohistochemistry technique and NanoString GeoMx techniques will be used for this purpose.
Postoperative complications
时间窗: After participant finishes trial and when last follow up (5 years from surgery) date is due.
Assessment of postoperative complications based on the Clavien-Dindo Score (CD) ranging from I to V, where I is any decline from normal postoperative course and V is death of patient.
Survival 90-days after surgery
时间窗: After participant finishes trial and when last follow up (5 years from surgery) date is due.
Assessment of survival 90 days after surgery.
Immune cells and subtypes in blood samples
时间窗: Through study completion. At latest within 1 year from last participant completes trial.
Assessing the number and subsets of immune cells in the obtained blood samples before and after propranolol treatment and between the two arms (propranolol versus placebo). This will be examined through FlowCytometry.
RNA-level gene expression in blood samples.
时间窗: Through study completion. At latest within 1 year from last participant completes trial.
RNA-level expression of genes related to immune-surveillance through NanoString nCounter technique.
次要结局
- Safety of 40 mg propranolol twice daily on blood pressure.(Through study completion, within 14 days after surgery.)
- Safety of 40 mg propranolol twice daily on heart rate.(Through study completion, within 14 days after surgery.)