Effect of Remote Ischaemic Conditioning in Oncology Patients (ERIC-ONC)

April 14, 2020 updated by: University College, London

A Single Centre Double-blinded Randomized Placebo Controlled Pilot Study Investigating the Effect of Remote Ischaemic preConditioning in ONCology Patients Undergoing Chemotherapy (ERIC-ONC)

Cancer survival has improved steadily due to earlier detection and treatment. Despite the established efficacy of anthracycline chemotherapy, its damaging effects on the heart (cardiotoxicity) limits treatment and confers acute and long term adverse cardiovascular consequences. Protective strategies for the heart (cardioprotection) with iron binders (chelation), heart rate (beta blockade) and blood pressure (renin angiotensin inhibition) medications have demonstrated promise in adult cancer patients, but these treatments are typically prescribed only after significant changes in heart chamber size and pumping ability are detected by imaging investigations (myocardial dysfunction).

Furthermore, these conventional therapies are constrained by important side effects that affect bone marrow, blood pressure, and the kidneys.

Remote ischaemic conditioning (RIC) protects the heart by activating cell survival pathways through brief repeated inflations and deflations of a blood pressure cuff to limit blood flow temporarily (noninjurious ischaemia). These innate survival mechanisms prevent part of the cellular injury that occurs during the ischaemia reperfusion cascade during a heart attack (myocardial infarction). Ischaemia reperfusion injury also shares common biochemical pathways with anthracycline cardiotoxicity, and thus RIC may be a novel form of nonpharmacological cardioprotection that can be applied when undergoing anthracycline chemotherapy.

The investigators propose a pilot single centre randomised controlled trial to investigate the effect of RIC on reducing heart muscle damage (myocardial injury) in anthracycline-treated cancer patients. The investigators will assess subclinical myocardial injury using high-sensitivity blood tests (troponin T levels) and advanced imaging techniques, monitor heart rhythm disturbances (cardiac arrhythmia) and analyse metabolic changes in urine and blood during chemotherapy, at specified time points, and follow up to 5 years after completing chemotherapy treatment).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

This pilot study aims to demonstrate whether remote ischaemic preconditioning (RIC), delivered as a nonpharmacological treatment via repeated inflations and deflations of a limb blood pressure cuff, can reduce subclinical myocardial injury from anthracycline chemotherapy. Chemotherapy cardiotoxicity is the dose limiting constraint in anthracycline chemotherapy regimens, and conventional drug treatments to prevent and treat it are limited by important interactions with blood pressure, kidney function or bone marrow function. The lifetime cancer risk is between 1 in 2 and 1 in 3 in the general population. Cancer treatment and survival has improved steadily 50% of patients now survive their initial cancer diagnosis, but approximately 25 to 50% of survivors will have abnormal cardiac function over the next twenty years. Historically, anthracycline chemotherapy dosing has been stratified to limit the incidence of clinical heart failure to around 5%. More recent studies have reported at least one third of anthracycline chemotherapy patients demonstrate a significant rise in Troponin levels as a blood biomarker of subclinical myocardial injury as well as documented evidence of biomarker rise even after a single cycle of chemotherapy, and thus the absolute threshold for myocardial injury may be lower and thus more prevalent than these conservative figures.

In standard dosing regimens, chemotherapy may be delayed or suspended in cancer patients based on the simplified measure of ejection fraction (EF) as a measure of cardiac systolic function. Conventional heart failure treatments such as betablockers or ACE inhibitors are usually prescribed only after a significant fall in EF, even though myocardial injury occurs long before this imprecise measurement changes. RIC has been shown to reduce myocardial injury and improve outcomes in elective and emergency percutaneous coronary intervention (PCI) and elective coronary artery bypass graft surgery (CABG). The common biochemical pathways in ischaemia reperfusion and anthracycline-induced cardiac myocyte injury suggest that RIC may be an unexplored nonpharmacological treatment to reduce myocardial injury for cancer patients.

This pilot study aims to demonstrate the effectiveness of RIC as an elegant noninvasive, nonmedicinal treatment to reduce myocardial injury in cancer patients, and therefore poses no significant ethical issues. RIC is known to be a safe intervention with no known significant adverse effects. Some patients have reported mild discomfort during cuff inflation. A small number have experienced minor skin bruising at the cuff site which is transient. There are no known long term adverse effects of RIC,

Recruitment Patients will be identified by their usual oncology team, and referred to the cardiology team based solely on known inclusion and exclusion criteria, which will ensure this process is free from undue influence.

The benefits of the study include an increase in the scientific understanding of how RIC may lead to a reduction in myocardial injury, as well as longitudinal documentation of myocardial injury in the form of blood biomarkers, ECG changes, metabolic changes, and novel imaging markers in cancer patients undergoing a common form of chemotherapy.

Study Type

Interventional

Enrollment (Anticipated)

128

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 Contact Backup

Study Locations

  • United Kingdom
      • London, United Kingdom, WC1E 6BT
        • Recruiting
        • University College London Hospitals
        • Contact:
        • Contact:
        • Principal Investigator:
          • Derek M Yellon, DSc FACC FAHA
        • Principal Investigator:
          • Malcolm Walker, MD FRCP
        • Sub-Investigator:
          • Robin Chung, MBBS MRCP
        • Sub-Investigator:
          • Michael Mallouppas, MRCP
        • Sub-Investigator:
          • Alison Macklin, BSc

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

14 years to 78 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Adult or teenage young adult cancer patients with capacity
  • Anthracycline-regimen chemotherapy (de novo or re-challenge)
  • Able to tolerate peripheral blood pressure arm cuff inflation

Exclusion Criteria:

  • Recent myocardial infarction in previous 4 weeks
  • previous diagnosis of dilated, hypertrophic cardiomyopathy, amyloid or Anderson-Fabry Disease
  • peripheral vascular disease
  • Chronic Kidney Disease (estimated glomerular filtration rate (GFR) < 30 ml/min)
  • Taking sulphonylureas
  • lymph node dissection patients will need BP cuff on contra-lateral arm
  • Skip remote ischaemic conditioning (RIC) cycle if very low platelets (e.g. platelets < 50 x 10^9/L, can have RIC when platelet counts recover, as per protocol).

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: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Remote ischaemic conditioning
Remote ischaemic conditioning in the form of a blood pressure cuff on upper arm inflated upto 200 mm Hg (or systolic BP + 20 mm Hg if low platelets e.g. 50-150 x10^9/L, skip remote ischaemic conditioning (RIC) if platelets < 50 x 10^9/L) for 5 minutes, then deflated to 0 mm Hg for 5 minutes, for 4 cycles before beginning of chemotherapy infusion. The entire pre-conditioning phase will last 40 minutes.
Procedure: Remote Ischaemic Conditioning
each cycle of Remote Ischaemic Conditioning (RIC) consists of inflating a blood pressure cuff on the upper limb (arm) upto 200mm Hg (systolic BP + 20 mm Hg for low platelets, e.g. 50-150 x 10^9/L; skip RIC if platelets < 50 x 10^9/L) for 5 minutes, then deflated to 0 mm Hg for 5 minutes.
Other Names:
  • Remote Ischaemic PreConditioning
  • Remote Ischemic Conditioning
Placebo Comparator: Control
Blood pressure cuff on upper arm inflated to 10 mm Hg for 5 minutes, then deflated to 0 mm Hg for 5 minutes, for 4 cycles before beginning of chemotherapy infusion. The entire control comparator will last 40 minutes
Other: Placebo
Sham control blood pressure cuff placement at 10 mm Hg for 5 minutes, then deflated to 0 mm Hg for 5 minutes.
Other Names:
  • Sham

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
hs-Troponin T (hs-TnT) levels
Time Frame: at baseline, at 3-24 hours after end of infusion of each chemotherapy cycle, then at initiation of chemotherapy infusion (cycles 2-6, occurring at intervals of 3-weeks), then at 1-, 3-, 6-, 12- months follow up
Biomarker of myocardial injury using high-sensitivity Troponin-T for above time points as serial measurements.
at baseline, at 3-24 hours after end of infusion of each chemotherapy cycle, then at initiation of chemotherapy infusion (cycles 2-6, occurring at intervals of 3-weeks), then at 1-, 3-, 6-, 12- months follow up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Major Adverse Clinical Cardiovascular Event (MACCE)
Time Frame: 1-, 3-, 6-, 12- months follow up
Major Adverse Cardiovascular Event (myocardial infarction, clinical heart failure requiring admission, life-threatening arrhythmia atrioventricular (AV) block requiring pacemaker, cardiac or cancer death)
1-, 3-, 6-, 12- months follow up
Echocardiographic global longitudinal strain (GLS)
Time Frame: at baseline, then at 3- and 12- months follow up
Echocardiographic longitudinal function (GLS %)
at baseline, then at 3- and 12- months follow up
Incidence of cardiac arrhythmia
Time Frame: at start of infusion of cycle 5 chemotherapy
two weeks ambulatory electrocardiographic (ECG) monitoring for atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, atrioventricular block
at start of infusion of cycle 5 chemotherapy
Biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP)
Time Frame: at 3- months follow up
for heart failure / raised left atrial pressure
at 3- months follow up
Micro ribonucleic acid (RNA) and mitochondrial de-oxyribonucleic acid (DNA) analysis
Time Frame: at baseline and at 3-months follow up
Comparison of changes in micro ribonucleic acid (miRNA) and mitochondrial deoxyribonucleic acid (mtDNA), markers of protein expression at baseline (before) and at 3-months' follow up after completing chemotherapy regimen
at baseline and at 3-months follow up

Collaborators and Investigators

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

Sponsor

University College, London

Collaborators

University College London Hospitals

Investigators

  • Principal Investigator: Derek M Yellon, PhD FACC FAHA, University College, London
  • Principal Investigator: Malcolm Walker, MD FRCP, University College London Hospitals
  • Study Director: Alison Macklin, University College London Hospitals

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

Helpful Links

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 16, 2015

Primary Completion (Anticipated)

December 1, 2020

Study Completion (Anticipated)

December 1, 2021

Study Registration Dates

First Submitted

May 5, 2015

First Submitted That Met QC Criteria

June 10, 2015

First Posted (Estimate)

June 15, 2015

Study Record Updates

Last Update Posted (Actual)

April 15, 2020

Last Update Submitted That Met QC Criteria

April 14, 2020

Last Verified

April 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 15/0276

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

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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