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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Zealand University Hospital

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Digestive System Diseases [C06]

Trial duration

23 Apr 2024 → ongoing

Decision date (initial)

2023-11-07

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Safety, Pharmacogenetic

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.

Conditions and MedDRA coding

Pancreatic ductal adenocarcinoma (PDAC)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Patients with suspected surgically resectable pancreatic cancer. Indication for surgical treatment with curative intend. Patients minimum 18 years old. Patients who can provide written informed consent.

Exclusion criteria 1

1. 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). Currently untreated pheochromocytoma. History of Prinzmetals angina. History of sick sinus syndrome or atrioventricular block. Recent or present (within 1 months) use of propranolol or any other beta-blocker. Recent or present (within 1 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Anxiety levels measured by The Hamilton Anxiety Rating Scale (HAM-A) and by The Hospital Anxiety and Depression Scale (HADS). The European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QoL) for pancreatic cancer will be used to assess quality of life. HRV data calculated from continuous ECG gathered by a Holter monitor. Follow up data: postoperative complications, survival 30-, 90- days and 1, 3-, 5- years after surgery. Blood and tissue sampling

Secondary endpoints 1

1. Safety: Changes in resting HR and BP during the intervention. Symptoms and side effects to medicine: light-headedness, lethargy, hypotension, bradycardia and other symptoms/side-effects. Tertiary end points: feasibility and implementation using the APEASE framework

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Zealand University Hospital

Sponsor organisation

Zealand University Hospital

Address

Lykkebaekvej 1

City

Koege

Postcode

4600

Country

Denmark

Scientific contact point

Organisation

Zealand University Hospital

Contact name

Ismail Gögenur

Public contact point

Organisation

Zealand University Hospital

Contact name

Ismail Gögenur

Third parties 1

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications