REmote iSchemic condItioning in Lymphoma PatIents REceiving ANthraCyclinEs

Study Overview
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Brief Summary
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Multinational, prospective, proof of concept phase II, double-blinded, sham-controlled, randomized clinical trial (RCT) to evaluate the efficacy and safety of Remote Ischaemic PreConditioning (RIPC) in Lymphoma patients receiving anthracyclines.

Detailed Description
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Multinational, prospective, proof of concept phase II, double-blinded, sham-controlled, randomized clinical trial (RCT) to evaluate the efficacy and safety of Remote Ischaemic PreConditioning (RIPC) in lymphoma patients receiving anthracyclines. Patients scheduled to undergo ≥5 chemotherapy cycles will be eligible. Patients fulfilling all inclusion and no exclusion criteria will be enrolled and undergo baseline Cardiac Magnetic Baseline (CMR), and high sensitivity troponin (hsTn) and NT-proBNP blood test. Patients with confirmed LVEF >40% by CMR will be randomized 1:1 to RIPC vs simulated RIPC (Sham). After the third chemotherapy cycle, a second CMR+ hsTn/ NT-proBNP will be performed for the validation of the early marker of cardiotoxicity. A third hsTn/ NT-proBNP blood test will be performed in the last chemotherapy cycle. Nine weeks after finishing chemotherapy, a last CMR+ hsTn/ NT-proBNP will be performed. Patients will be followed-up for clinical events at 6, 12, 18, 30 and 42 months until the last patient undergoes the final CMR. When the last patient undergoes the third CMR, the follow-up will be closed. The median follow-up estimation for clinical endpoints is 24 months (range: 6 to 42 months).

Official Title
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REmote iSchemic condItioning in Lymphoma PatIents REceiving ANthraCyclinEs

Conditions
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Anthracycline-induced Cardiac Toxicity, Lymphoma

Intervention / Treatment
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* Device: RIPC
* Device: Simulated RIPC (Sham)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old First Lymphoma diagnosis Scheduled to undergo ≥5 chemotherapy cycles including anthracyclines. Pre-chemo LVEF >40% on screening echocardiography. Presence of ≥1 of the following risk factors for developing cardiotoxicity: Previous coronary artery disease (any of the following): Previous coronary revascularisation (PCI or CABG) or Medical history of previous significant nonrevascularized coronary stenosis Previous Acute Coronary Syndrome / Acute Myocardial Infarction with a LVEF > 40 LVEF 41-54% Age ≥ 65 years old Previous diagnosis of arterial hypertension (with or without treatment) Chronic kidney disease (estimated glomerular filtration rate <60ml/min/1.73m2) Current or former smoker. Obesity (BMI≥30 kg/m2) LVH on screening echocardiography (LV thickness ≥12mm). High alcohol intake (≥21 alcoholic beverages per week) Sinus rhythm on screening ECG Previous diagnosis of diabetes (except those treated with sulfonylureas or those with neuropathy) Previous non-anthracycline-based chemotherapy Signed Informed Consent Form (ICF) Exclusion Criteria: History of any of the following diseases: Any cancer who received anthracyclines treatment before the index episode. Previous clinical diagnosis of heart failure. Permanent atrial fibrillation (AF). Severe valvular or sub-valvular heart disease. Severe peripheral arterial disease in the upper extremities or arteriovenous (AV) shunt in the arm selected for RIPC. Clinical diagnosis of diabetes neuropathy Contraindication for CMR: Severe claustrophobia. Any device which is known to threaten or pose hazard in all MR environments (http://www.mrisafety.com/). Patients with implanted biomedical cardiac devices: pacemakers, ICDs or CRT. Severe thrombocytopenia (platelets <50,000/µL) on any blood test within the previous 3 months. Patients participating in other clinical trials. Impossibility to consent or undergo study follow-ups.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization (1:1) will be stratified by LVEF on baseline CMR (as quantified by CMR core lab /CNIC), by research Centre and by patient's gender.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Remote Ischemic Conditioning<br>Remote Ischemic Conditioning (RIC): Patients will undergo weekly RIC during the entire span of the chemotherapy period. Each RIC session will include four cycles of 5 min blood pressure cuff inflation followed by 5 min deflation | Device: RIPC<br>* The procedure will be performed by using an electric auto-control device (modified blood pressure monitor for remote ischemic conditioning, Seagull Healthcare Aps, Denmark) for Remote Ischemic Conditioning in the arm. During the inflation period, the blood pressure cuff is inflated to 200 mmHg to stop blood flow in the arm.<br>|
| Sham Comparator: simulated RIPC (Sham)<br>Control group (Sham): Patients will undergo weekly simulated RIC (sham) during the entire span of the chemotherapy period. Each sham session will include four cycles of 5 min blood pressure cuff inflation followed by 5 min deflation. | Device: Simulated RIPC (Sham)<br>* The procedure will be performed by using an electric auto-control device (modified blood pressure monitor for remote ischemic conditioning, Seagull Healthcare Aps, Denmark) for Remote Ischemic Conditioning in the arm. During the inflation period, the blood pressure cuff is inflated to a low pressure not stopping blood flow in the arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary efficacy endpoint: (RIC vs Sham) Absolute change in LVEF | change in LVEF between baseline and any follow-up CMRs, whichever shows worse LVEF UNITS: LVEF is expressed as % LVEF= (LV end-diastolic volume - LV end-systolic volume) / LV end-systolic volume), % | 9 weeks after the last chemotherapy cycle (anticipated to be between 150 and 200 days from enrollment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of anthracycline-induced cardiotoxicity events | Cardiotoxicity event is defined as one of the following: Drop in LVEF between study CMRs of ≥10 absolute points regardless the absolute value of follow- up ejection fraction (EF). Drop in LVEF between study CMRs of ≥5 to <10 absolute points with a follow-up EF value <50% UNITS: absolute number of patients in each arm qualifying for cardiotoxicity event (i.e. each patient will be qualified at the end of the study as YES/NO). | 9 weeks after the last chemotherapy cycle (anticipated to be between 150 and 200 days from enrollment) | 
| Rate of tumor regression. | Response to chemotherapy UNITS: absolute number of patients in each arm qualifying as responder or no responder (i.e. each patient will be qualified at the end of the study as YES/NO). | 9 weeks after the last chemotherapy cycle (anticipated to be between 150 and 200 days from enrollment) | 
| Change in Quality of Life-Haematological Malignancy Patient-Reported Outcome Measure questionnaire | Haematological Malignancy Patient-Reported Outcome Measure (HM-PRO) questionnaire UNITS: absolute points in the questionnaire. minimum value 0 maximum value 84 the higher the total score, the better (greater the effect on a patient's QoL) | 9 weeks after the last chemotherapy cycle (anticipated to be between 150 and 200 days from enrollment) | 
| Change in Quality of Life-Euro Quality of Life-5 dimensions questionnaire | Euro Quality of Life-5 dimensions (EuroQoL-5D) questionnaire: UNITS: absolute points in the questionnaire. minimum value 0 maximum value 100 the higher the total score, the better (greater the effect on a patient's QoL) | 9 weeks after the last chemotherapy cycle (anticipated to be between 150 and 200 days from enrollment) | 
| Change in Quality of Life-Kansas City Cardiomyopathy Questionnaire | Kansas City Cardiomyopathy Questionnaire (KCCQ-12) UNITS: absolute points in the questionnaire. minimum value 0 maximum value 65 the higher the total score, the better (greater the effect on a patient's QoL) | 9 weeks after the last chemotherapy cycle (anticipated to be between 150 and 200 days from enrollment) | 
| Rate of Heart Failure Hospitalization | Rate of Heart Failure Hospitalization UNITS: Absolute number of patients in each arm experiencing a heart failure hospitalization | 6-42 months |