Prehabilitation to Improve Heart Rate Variability (PRIME) (PRIME)

August 5, 2025 updated by: Giovanni Landoni, Università Vita-Salute San Raffaele

Prehabilitation to Improve Heart Rate Variability In Surgical Cancer Patients: a randoMized controllEd Trial

Cancer patients require chronic management and care. For those individuals living with cancer, a comprehensive approach that acknowledges the interdisciplinary nature of their condition can help guide appropriate care strategies and support their overall well-being. Approximately 45% of patients diagnosed with cancer undergo surgery to remove their tumor. Despite the advancements in surgical techniques, anesthesia, and perioperative care, major cancer surgeries still pose a significant challenge leading to a considerable decline in physiological and functional capacity. Traditionally, efforts focused on postoperative rehabilitation to enhance recovery. Recently, prehabilitation, a form of rehabilitation which aims to improve functional capacity before surgery, has gained attention for its potential benefits in improving surgical outcomes. However, prehabilitation lacks objective assessment measures to evaluate its effectiveness. Developing validated outcome measures is essential to enhance the impact of prehabilitation on surgical outcomes and long-term care for cancer patients. Heart rate variability (HRV) is a physiological parameter that measures the variation in time intervals between consecutive heartbeats, reflecting the autonomic nervous system activity which might serve as a valuable solution for objective outcome measures in evaluating the effectiveness of prehabilitation for cancer patients, providing an objective tool to assess and monitor physiological response to stress, recovery capacity, and autonomic nervous system activity. A multicenter randomized controlled trial will be conducted to assess the impact of a multimodal prehabilitation program on HRV. Patients aged 18 or older, scheduled for elective major cancer surgery will be randomized to receive either prehabilitation or standard care. The prehabilitation arm will receive a program involving home-based physical, nutritional, and psychological interventions for at least four weeks. Participants allocated to the control group will receive usual care. Patients will be followed throughout the study using an innovative mobile application, allowing for real-time monitoring and data collection during the prehabilitation program. The study has two primary outcomes: A) to assess the impact of prehabilitation on increasing preoperative HRV in chronic cancer patients undergoing surgery; B) to assess the effect of prehabilitation on length of hospital stay.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Cancer patients require long-term management and ongoing care due to the chronic nature of their condition. Major cancer surgeries pose significant challenges, resulting in a decline in physiological and functional capacity. Traditionally, postoperative rehabilitation has been the most suitable intervention to improve functional recovery. Prehabilitation, which aims to enhance patients' functional capacity before surgery and to improve patients' ability to cope with physiological stress, is considered the best form of rehabilitation. Through multimodal strategies like exercise, nutrition and psychological support, prehabilitation can improve surgical outcomes for cancer patients. However, prehabilitation lacks objective assessment measures. Heart rate variability (HRV), a physiological parameter measuring variation in heartbeats, reflects autonomic nervous system activity and an increase in HRV is associated with fitness and recovery capacity in sports medicine. Psychological factors, nutritional status and physical exercise influence HRV. Hence, HRV could be used to objectively assess prehabilitation interventions. In addition, HRV is widely used in risk assessment in cardiology, and a reduction in HRV is recognized to be associated with complications and mortality. Despite its evident potential in risk assessment, HRV has never been utilized in preoperative assessments.

This is an international, multicenter, parallel-group, randomized study in chronic cancer patients undergoing surgery. Adult men and women patients who are eligible according to the inclusion/exclusion criteria will be randomized to study the effect of prehabilitation versus standard care on heart rate variability (HRV).

A total of 600 patients will be recruited by systematic screening of patients scheduled for elective surgical procedures. All patients undergoing major cancer surgery will be screened for eligibility and those who meet the inclusion/exclusion criteria will be approached for consent. Research personnel will use a web-based randomization system to assign patients (1:1 ratio) to either the prehabilitation or control arm. Study personnel will also collect data on recruitment rates, with reasons for non-enrollment.

Eligible patients will be randomly assigned to one of two treatments:

  1. Multimodal prehabilitation program for four weeks starting as soon as possible before surgery;
  2. Standard care.

The multimodal prehabilitation program will be individualized by carefully integrating and adapting various components to meet individual needs. The program will last four weeks (plus maintenance in case of delayed surgery), and will incorporate exercise training, nutritional therapy, and anxiety reduction techniques. After enrollment, patients will receive initial contact from trained personnel through telemedicine. To ensure personalized care, a comprehensive assessment will be conducted to identify specific physical, nutritional, or psychological challenges. Based on this assessment, a customized intervention plan will be prescribed to achieve tailored exercise training, optimized nutrition, and effective distress-coping strategies. Patients will be requested to download a dedicated smartphone application, which will comprehensively monitor and track their progress towards achieving their prehabilitation goals. After completing the four-week program, patients will continue a maintenance program until surgery.

The first HRV measurement will be performed for 5 minutes in an isolated room, after signing the written consent and before randomization, on the day of screening which occurs several weeks before surgery. The second HRV measurement will be performed the day before surgery. Both HRV time-domain measurements and HRV frequency-domain measurements will be evaluated.

Study Type

Interventional

Enrollment (Estimated)

600

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Catania, Italy, 95100
        • Active, not recruiting
        • Azienda Ospedaliero Universitaria Policlinico San Marco di Catania
      • Foggia, Italy, 71100
        • Recruiting
        • Università di Foggia
        • Contact:
      • Milano, Italy, 20132
        • Recruiting
        • IRCCS Ospedale San Raffaele
        • Contact:
      • Pisa, Italy, 56126
        • Recruiting
        • Azienda Ospedaliero Universitaria Pisana
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Scheduled to undergo elective major abdominal or thoracic cancer surgery;
  2. Scheduled to undergo surgery at least three weeks after enrollment;
  3. Age ≥ 18 years;
  4. Provide written informed consent;
  5. Willing and able to use smartphone application.

Exclusion Criteria:

  1. Presenting with very poor functional capacity;
  2. American Society of Anesthesiologists (ASA) physical status classes 5-6;
  3. Disabling orthopedic, neuromuscular, and psychiatric diseases or other conditions that preclude participation in a prehabilitation program.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Prehabilitation
Prehabilitation arm groups will receive preoperative intervention which includes exercise training, nutritional therapy and anxiety reducing techniques, aimed at preventing or attenuating surgery-driven functional decline.
Behavioral: Multimodal prehabilitation program

A tailored intervention will be prescribed if specific physical, nutritional or psychological impairments will be identified during the assessment phase. Based on the data obtained during the multimodal assessment, different domains and levels of care will be prescribed, focusing on exercise training, and/or nutrition optimization, and/or distress-coping techniques. Different combinations of these three domains will be utilized to maximize their synergistic anabolic effect.

The duration of the program will be set at 4 weeks.
No Intervention: Control group
Standard care treatment: application of ERAS pathways (Enhanced Recovery After Surgery)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assess the impact of prehabilitation on heart rate variability
Time Frame: Preoperative
This primary outcome measure will be the change in the standard deviation of normal-to-normal intervals (SDNN) from baseline to the day before surgery.
Preoperative
Days at home within first 30 days after surgery
Time Frame: 30-days after surgery
The mean number of days at home in the first 30 days after surgery will be compared between groups
30-days after surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quality of life at 30 days
Time Frame: 30-days after surgery
Assess quality of life in the first 30 days at home after surgery using the EuroQol-5 Dimension (EQ-5D-5L) questionnaire, a validated tool for evaluating health-related quality of life. The outcome will be reported as the mean EQ-5D-5L index score and the mean EQ-VAS score measured at 30 days postoperatively.
30-days after surgery
30-days postoperative complication
Time Frame: 30-days after surgery
Assess the occurrence of postoperative complications in the first 30 days after surgery
30-days after surgery
Correlation between preoperative standard deviation of all normal to normal R-R intervals (SDNN) and quality of life at 30 days postoperatively
Time Frame: 30-days after surgery
Investigate the association between preoperative heart rate variability (HRV) and life at 30 days postoperatively
30-days after surgery
Correlation between preoperative SDNN and DAH-30
Time Frame: 30-days after surgery
Investigate the association between preoperative heart rate variability (HRV) and the days alive and at home within 30 days after surgery (DAH-30)
30-days after surgery
Correlation between preoperative SDNN and postoperative complication
Time Frame: 30-days after surgery
Investigate the association between preoperative heart rate variability (HRV) and postoperative complication
30-days after surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Università Vita-Salute San Raffaele

Collaborators

Dott. Fabio Guarracino
Prof. Gilda Cinnella
Dott. Filippo Sanfilippo

Investigators

  • Principal Investigator: Fabio Guarracino, Doctor, Azienda Ospedaliero, Universitaria Pisana

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 20, 2024

Primary Completion (Estimated)

August 1, 2026

Study Completion (Estimated)

November 1, 2026

Study Registration Dates

First Submitted

December 12, 2024

First Submitted That Met QC Criteria

December 19, 2024

First Posted (Actual)

December 20, 2024

Study Record Updates

Last Update Posted (Actual)

August 6, 2025

Last Update Submitted That Met QC Criteria

August 5, 2025

Last Verified

August 1, 2025

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • PNRR-MCNT2-2023-12377934

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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