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

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ClinicalTrials.gov Identifier: NCT02471885
Recruitment Status : Recruiting
First Posted : June 15, 2015
Last Update Posted : April 15, 2020
Sponsor:
Collaborator:
University College London Hospitals
Information provided by (Responsible Party):
University College, London

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
Cardiotoxicity Procedure: Remote Ischaemic Conditioning Other: Placebo Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 128 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Single Centre Double-blinded Randomized Placebo Controlled Pilot Study Investigating the Effect of Remote Ischaemic preConditioning in ONCology Patients Undergoing Chemotherapy (ERIC-ONC)
Actual Study Start Date : December 16, 2015
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021

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 Name: Sham




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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)

  2. Echocardiographic global longitudinal strain (GLS) [ Time Frame: at baseline, then at 3- and 12- months follow up ]
    Echocardiographic longitudinal function (GLS %)

  3. 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

  4. Biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) [ Time Frame: at 3- months follow up ]
    for heart failure / raised left atrial pressure

  5. 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



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Ages Eligible for Study:   16 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02471885


Contacts
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Contact: Robin Chung, MBBS MRCP 02034479880 r.chung@ucl.ac.uk
Contact: Michael Mallouppas, MBBS MRCP 02034479880 m.mallouppa@ucl.ac.uk

Locations
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United Kingdom
University College London Hospitals Recruiting
London, United Kingdom, WC1E 6BT
Contact: Robin Chung, MBBS MRCP    02034479880    r.chung@ucl.ac.uk   
Contact: Michael Mallouppas, MRCP    02034479880 ext 02034479880    m.mallouppa@ucl.ac.uk   
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         
Sponsors and Collaborators
University College, London
University College London Hospitals
Investigators
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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
Additional Information:
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT02471885    
Other Study ID Numbers: 15/0276
First Posted: June 15, 2015    Key Record Dates
Last Update Posted: April 15, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by University College, London:
remote ischaemic conditioning
remote ischemic conditioning
cardio-oncology
anthracycline
troponin
chemotherapy
myocardial reperfusion injury
Additional relevant MeSH terms:
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Cardiotoxicity
Pathologic Processes
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Radiation Injuries
Wounds and Injuries