Prevention of Anthracycline-induced Cardiotoxicity (ICOS-ONE)

ICOS-ONE - Prevention of Anthracycline-induced Cardiotoxicity: a Multicentre Randomized Trial Comparing Two Therapeutic Strategies.

Anthracycline based anti-tumoral therapies are know to develop cardiac damage that could also lead to heart failure. Monocentric studies proved that a treatment with ACE inhibitors (ACEi) and betablockers (BB) during the first elevation of cardiac troponin is able to reduce the incidence of heart failure (HF).

ICOS-ONE trial is a multicenter randomized trial comparing two therapeutic strategies. The main objective is to assess whether enalapril started concomitantly to AC-containing treatments, can prevent cardiac toxicity more effectively than when enalapril is prescribed to selected patients showing laboratory evidences of injury after chemotherapy, during follow-up visits in 268 patients.

Study Overview

• Status: Active, not recruiting
• Conditions: Cancer
• Intervention / Treatment: Drug: Enalapril

Detailed Description

Anthracycline-containing chemotherapy is well known to cause dose-dependent, progressive cardiac damage in particular left ventricular dysfunction evolving to heart failure. The development of cardiac dysfunction, even asymptomatic, leads to the exclusion of cancer patients from effective chemotherapy, with a possible negative impact on their oncologic prognosis. The use of troponins (cTn) during cancer chemotherapy with anthracyclines (AC) allows to identify early cardiac injury before the onset of left ventricular dysfunction, with high predictive value. ACE inhibitors (ACEi) and betablockers (BB) prescribed to cancer patients when, during the course or after the end of a chemotherapy, signs or symptoms of cardiac failure are detected, have been shown to be protective in monocentric studies. Prophylaxis with an ACEi, enalapril and a BB, bisoprolol in patients treated with AC-chemotherapy may allow to reduce the risk of cardiovascular injury, allowing for the completion of the whole scheduled antitumoral treatment.

Sample size According to previous studies from the European Institute of Oncology IEO), an increase of circulating troponin levels is estimated to be 20% in the patients treated with anthracyclines at conventional dosage. 134 patients in each arm (Total sample size of 268 patients) are required to detect a 50% relative risk reduction in the incidence of elevated troponins levels at a 2-sided alpha=0.05 and a 1-beta=0.60, taking into account a 5% drop-out rate. This endpoint will allow to compare the strategy based on prevention (arm 1) with the strategy guided by troponin (arm 2). Given the originality of the proposal and the limited resources, this study will be exploratory in nature, waiting for a larger and adequately powered clinical trial designed to observe significant differences in clinical events.

Safety Tolerability of enalapril, valsartan and bisoprolol has been proven over several years and in broad populations of cardiac patients, not only with heart failure, but also at cardiovascular risk in the absence of signs or symptoms of HF. Specific unwanted effects in cancer patients are not expected, based on previous experiences. Special care should be taken to avoid profound hypotension induced by enalapril, valsartan and bisoprolol in these patients. Serious Adverse Events (SAEs) ad Suspected and Unsuspected Serious Adverse Reactions (SUSARs) will be collected and treated appropriately.

• Study Type: Interventional
• Enrollment (Estimated): 268
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy
    • European Institute of Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with diagnosis of cancer and indication for first- and second-line therapy with anthracyclines
2. Age ≥18years
3. Serum creatinine<177µmol/L(2mg/100mL)
4. Systolic blood pressure ≥100 mmHg and ≤170 mmHg
5. Left ventricular ejection fraction (VEF) >50%
6. Written informed consent.
7. Life expectancy of at least 12 months

Exclusion Criteria:

1. Patients with history or clinical/instrumental evidences of heart failure
2. Patients with history or clinical/instrumental evidences of ischemic heart disease;
3. Patients with blood troponin levels higher than the cut-off suggested by the manufacturer before starting cancer CT;
4. Systolic blood pressure<100 mmHg;
5. Heart rate<50 bpm;
6. Prior malignancy requiring potentially cardiotoxic chemotherapy (e.g. anthracyclines, trastuzumab..);;
7. Uncontrolled hypertension defined as systolic blood pressure>170 mmHg;
8. Treatment with ACEi, ARB or BB within 4 weeks prior to study start;
9. Known intolerance to enalapril, except for cough;
10. Planned treatment with dexrazoxane;
11. Participation in another experimental drug trial within 4 weeks prior to study start;
12. Non-cooperative behaviour or suspected poor compliance;
13. Psychiatric disorders or conditions that might impair the ability to give informed consent;
14. Pregnancy or breast feeding;
15. Scheduled mediastinal radiotherapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Enalapril concomitant; Enalapril started concomitantly to AC-containing treatments	Drug: Enalapril; Naprilene 5 mg tablets; Dosage: 2.5 to 10 mg/12h Duration of treatment: up to end of follow up; Other Names: naprilene
Experimental: Enalapril after injury; Enalapril prescribed to selected patients showing laboratory evidences of injury after chemotherapy at follow-up visits.	Drug: Enalapril; Naprilene 5 mg tablets; Dosage: 2.5 to 10 mg/12h Duration of treatment: up to end of follow up; Other Names: naprilene

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the occurrence of cTn elevation above the threshold in use at the local laboratory, at any time during the study	To assess whether enalapril administered concomitantly to anthracyclines (AC) containing treatments can prevent cardiac toxicity more effectively than enalapril prescribed to selected patients showing laboratory evidences of injury after chemotherapy (CT), at follow-up visits. Cardiac toxicity is measured on the basis of cardiac troponin levels.	up to 1 year after the completion of the anthracyclines containing chemotherapy.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
admissions to hospital for cardiovascular causes,	to assess whether enalapril administered concomitantly to AC-containing treatments can reduce admissions to hospital for cardiovascular causes	up to 3 years after the completion of the anthracyclines containing chemotherapy.
cardiovascular deaths	to assess whether enalapril administered concomitantly to AC-containing treatments can reduce cardiovascular deaths	up to 1 year after the completion of the anthracyclines containing chemotherapy.
occurrence of hypo- or hyperkinetic arrhythmias	to assess whether enalapril administered concomitantly to AC-containing treatments can reduce new occurrence of hypo- or hyperkinetic arrhythmias	up to 1 year after the completion of the anthracyclines containing chemotherapy.

Collaborators and Investigators

• Sponsor: European Institute of Oncology
• Investigators: Principal Investigator: Carlo Cipolla, MD, European Institute of Oncology

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2012
• Primary Completion (Actual): December 1, 2019
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: July 29, 2013
• First Submitted That Met QC Criteria: October 18, 2013
• First Posted (Estimated): October 23, 2013

Study Record Updates

• Last Update Posted (Actual): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 27, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: chemotherapy; cancer; anthracyclines
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Wounds and Injuries; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Cardiotoxicity; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Enalapril
• Other Study ID Numbers: IEO S701/412; 2012-002248-26 (EudraCT Number)