ERIC-ONC: Effect of Remote Ischaemic Conditioning in Oncology Patients

Sponsor

University College, London (Other)

Overall Status

Unknown status

CT.gov ID

NCT02471885

Collaborator

University College London Hospitals (Other)

128

Enrollment

Location

Arms

71.5

Anticipated Duration (Months)

1.8

Patients Per Site Per Month

Study Details

Study Description

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	N/A

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 Design

Study Type:

Interventional

Anticipated 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 :

Dec 16, 2015

Anticipated Primary Completion Date :

Dec 1, 2020

Anticipated Study Completion Date :

Dec 1, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

hs-Troponin T (hs-TnT) levels [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

Major Adverse Clinical Cardiovascular Event (MACCE) [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)
Echocardiographic global longitudinal strain (GLS) [at baseline, then at 3- and 12- months follow up]
Echocardiographic longitudinal function (GLS %)
Incidence of cardiac arrhythmia [at start of infusion of cycle 5 chemotherapy]
two weeks ambulatory electrocardiographic (ECG) monitoring for atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, atrioventricular block
Biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) [at 3- months follow up]
for heart failure / raised left atrial pressure
Micro ribonucleic acid (RNA) and mitochondrial de-oxyribonucleic acid (DNA) analysis [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University College London Hospitals	London		United Kingdom	WC1E 6BT

Sponsors and Collaborators

University College, London
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