Prevention of Left Ventricular Dysfunction During Chemotherapy

Multiple Myeloma Clinical Trial

— OVERCOME  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01110824
• Other study ID #: OVERCOME
• Secondary ID: 2007-006604-38FI
• Status: Completed
• Phase: Phase 3
• First received: April 23, 2010
• Last updated: November 14, 2013
• Start date: April 2008
• Est. completion date: March 2012

Study information

• Verified date: November 2013
• Source: Hospital Clinic of Barcelona
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: March 2012
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Autologous Hematopoietic Stem Cell Transplantation
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoid Neoplasm
• Lymphoma
• Multiple Myeloma
• Neoplasms, Plasma Cell
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Precursor-cell Lymphoblastic Leukemia-Lymphoma
• Ventricular Dysfunction
• Ventricular Dysfunction, Left

Intervention

Drug:
• Enalapril and carvedilol
Enalapril 2.5 to 10 mg BID Carvedilol 6.25 to 25 mg BID

Locations

Country	Name	City	State
Spain	Hospital Clinic	Barcelona	Catalunya
Spain	Hospital Clinic	Barcelona	Catalunya

Sponsors (3)

Lead Sponsor	Collaborator
Hospital Clinic of Barcelona	European Union, Instituto de Salud Carlos III

Country where clinical trial is conducted

Spain, 

References & Publications (2)

Bosch X, Esteve J, Sitges M, de Caralt TM, Domènech A, Ortiz JT, Monzó M, Morales-Ruiz M, Perea RJ, Rovira M. Prevention of chemotherapy-induced left ventricular dysfunction with enalapril and carvedilol: rationale and design of the OVERCOME trial. J Card Fail. 2011 Aug;17(8):643-8. doi: 10.1016/j.cardfail.2011.03.008. Epub 2011 May 6. — View Citation

Bosch X, Rovira M, Sitges M, Domènech A, Ortiz-Pérez JT, de Caralt TM, Morales-Ruiz M, Perea RJ, Monzó M, Esteve J. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in left ventricular ejection fraction (LVEF) measured by echocardiography and by cardiac magnetic resonance imaging (CMR).		6 months after randomization	No
Secondary	Incidence of death, heart failure or LV systolic disfunction (LVEF<45%)		6 months after randomization	No
Secondary	Assessment of genetic polymorphisms involved in chemotherapy-induced cardiotoxicity		Baseline	No
Secondary	Prognostic value for cardiac toxicity of troponin I and BNP		up to 3 months	No
Secondary	Right and left ventricular volumes measured by CMR		6 months after randomization	No
Secondary	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	No
Secondary	Incidence of an absolute decrease in LVEF>10 percent units associated with a decline below its normal limit of 50%		6 months after randomization	No
Secondary	Serious adverse events		6 months after randomization	Yes
Secondary	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	No