Clinical trial NCT02471885: Effect of Remote Ischaemic Conditioning in Oncology Patients
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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Cardiotoxicity
Keywords: remote ischaemic conditioning
remote ischemic conditioning
cardio-oncology
anthracycline
troponin
chemotherapy
myocardial reperfusion injury
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: University College London Hospitals
First posted: 2015-06-15
Enrollment: 128
Sex: ALL
Minimum age (years): 16
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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).

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.

Eligibility 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).

Primary outcomes:
measure: hs-Troponin T (hs-TnT) levels
timeFrame: 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 outcomes:
measure: Major Adverse Clinical Cardiovascular Event (MACCE)
timeFrame: 1-, 3-, 6-, 12- months follow up
measure: Echocardiographic global longitudinal strain (GLS)
timeFrame: at baseline, then at 3- and 12- months follow up
measure: Incidence of cardiac arrhythmia
timeFrame: at start of infusion of cycle 5 chemotherapy
measure: Biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP)
timeFrame: at 3- months follow up
measure: Micro ribonucleic acid (RNA) and mitochondrial de-oxyribonucleic acid (DNA) analysis
timeFrame: at baseline and at 3-months follow up
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: University College London Hospitals
Study officials:
affiliation: University College, London
name: Derek M Yellon, PhD FACC FAHA
role: PRINCIPAL_INVESTIGATOR
affiliation: University College London Hospitals
name: Malcolm Walker, MD FRCP
role: PRINCIPAL_INVESTIGATOR
affiliation: University College London Hospitals
name: Alison Macklin
role: STUDY_DIRECTOR
References:
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citation: Davies WR, Brown AJ, Watson W, McCormick LM, West NE, Dutka DP, Hoole SP. Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long-term follow-up. Circ Cardiovasc Interv. 2013 Jun;6(3):246-51. doi: 10.1161/CIRCINTERVENTIONS.112.000184. Epub 2013 May 21.
citation: Chung R, Maulik A, Hamarneh A, Hochhauser D, Hausenloy DJ, Walker JM, Yellon DM. Effect of Remote Ischaemic Conditioning in Oncology Patients Undergoing Chemotherapy: Rationale and Design of the ERIC-ONC Study--A Single-Center, Blinded, Randomized Controlled Trial. Clin Cardiol. 2016 Feb;39(2):72-82. doi: 10.1002/clc.22507. Epub 2016 Jan 25.