OVERCOME: Prevention of Left Ventricular Dysfunction During Chemotherapy

Sponsor

Hospital Clinic of Barcelona (Other)

Overall Status

Completed

CT.gov ID

NCT01110824

Collaborator

Instituto de Salud Carlos III (Other), European Union (Other)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The investigators' objective is to assess the efficacy of the combined treatment with enalapril and carvedilol in the prevention of left ventricular systolic dysfunction in patients with hematological malignancies submitted to intensive chemotherapy with potential cardiotoxicity.

The hypothesis is that these drugs administered during chemotherapy may prevent left ventricular systolic dysfunction.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Precursor-cell Lymphoblastic Leukemia-Lymphoma Lymphoid Neoplasm Multiple Myeloma Lymphoma Autologous Hematopoietic Stem Cell Transplantation	Drug: Enalapril and carvedilol	Phase 3

Detailed Description

The prognosis of patients with hematological malignancies has greatly improved in the last years with the use of new chemotherapeutic drugs and regimens at the cost of significant adverse events such as cardiac toxicity. Asymptomatic left ventricular systolic dysfunction limits the specific treatment of the patients and their long-term survival, since a significant proportion of them will relapse within 5 years after front-line therapy and will require further salvage treatment, including hematopoietic stem-cell transplantation in most instances.

Angiotensin-converting enzyme inhibitors (ACEIs) have showed to have preventive effects against chemotherapy-induced cardiotoxicity in animal models, and in patients with early cardiotoxicity. Carvedilol prevent free radical release, mitochondrial dysfunction, apoptosis, and dilated cardiomyopathy in animals treated with anthracyclines, and have shown promising results in preventing chemotherapy-induced left ventricular dysfunction in patients.

As demonstrated in post-infarction patients, the combined treatment with an ACEI and carvedilol could have additive effects to prevent LV dysfunction in patients with hematological malignancies at high risk of cardiac toxicity. Therefore, we designed the OVERCOME (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies) study, a prospective, randomized trial to evaluate the combined effect of enalapril and carvedilol on the prevention of left ventricular dysfunction in patients with malignant hemopathies undergoing intensive chemotherapy.

Study Design

Study Type:

Interventional

Actual Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Prevention of Left Ventricular Dysfunction With Enalapril and Carvedilol in Patients Submitted to Intensive Chemotherapy for the Treatment of Malignant Hemopathies

Study Start Date :

Apr 1, 2008

Actual Primary Completion Date :

Dec 1, 2011

Actual Study Completion Date :

Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enalapril and carvedilol Enalapril 2.5 to 10 mg BID plus Carvedilol 6.25 to 25 mg BID	Drug: Enalapril and carvedilol Enalapril 2.5 to 10 mg BID Carvedilol 6.25 to 25 mg BID
No Intervention: Control Control arm without intervention

Arm

Intervention/Treatment

Experimental: Enalapril and carvedilol

Enalapril 2.5 to 10 mg BID plus Carvedilol 6.25 to 25 mg BID

Drug: Enalapril and carvedilol

Enalapril 2.5 to 10 mg BID Carvedilol 6.25 to 25 mg BID

No Intervention: Control

Control arm without intervention

Outcome Measures

Primary Outcome Measures

Change from baseline in left ventricular ejection fraction (LVEF) measured by echocardiography and by cardiac magnetic resonance imaging (CMR). [6 months after randomization]

Secondary Outcome Measures

Incidence of death, heart failure or LV systolic disfunction (LVEF<45%) [6 months after randomization]
Assessment of genetic polymorphisms involved in chemotherapy-induced cardiotoxicity [Baseline]
Prognostic value for cardiac toxicity of troponin I and BNP [up to 3 months]
Right and left ventricular volumes measured by CMR [6 months after randomization]
Subgroup analysis by diagnosis (acute leukemia vs. other malignant hemopathies submitted to autologous peripheral blood stem cell transplantation), and positive biomarkers (TnI, BNP). [6 months after randomization]
Incidence of an absolute decrease in LVEF>10 percent units associated with a decline below its normal limit of 50% [6 months after randomization]
Serious adverse events [6 months after randomization]
the incidence of LV dysfunction as assessed by the measurement of the LV strain, and of diastolic dysfunction measured by echo-Doppler [6 months after randomization]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult patients 18-70 years old
Sinus rhythm
Normal LVEF (>=50%)
Patients recently diagnosed of acute leukemia to be submitted to intensive chemotherapy or
Patients with other hemopathies submitted to autologous peripheral blood stem cell transplantation
Signed informed consent

Exclusion Criteria:

Congestive heart failure
LVEF<50%
Coronary artery disease,
significant valvulopathy or myocardiopathy
Renal failure (MDRD<30)
Liver failure
Ongoing or expected need to be treated with angiotensin-converting enzyme inhibitors (ACE-i),angiotensin II receptor blockers (ARB) or beta-blockers
Prior allergy to ACEI or ARB
Systolic blood pressure <90 mmHg
Asthma
Auriculoventricular (AV) block or sinus bradycardia (HR<60 bpm)
Persistent atrial fibrillation
Need to be treated with Class I antiarrhythmic drugs
Pregnancy
Inability or unwillingness to give unformed consent