Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors

Study ID
STU 042016-019

Study Sites

  • UT Southwestern Ambulatory Services

Contact
Beverly Kleiber
2144566484
beverly.kleiber@childrens.com

Principal Investigator
Daniel Bowers, M.D.

Official Title

Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Heart Failure (PREVENT-HF): A Phase 2b Randomized Placebo-Controlled (Carvedilol) Trial

Brief Overview

This randomized phase IIb trial studies how well low-dose carvedilol works in preventing heart failure in cancer survivors exposed to high dose anthracyclines for management of childhood cancer. Patients who received high-dose anthracycline chemotherapy are at a much greater risk for developing heart failure compared to survivors who didn't get any anthracycline chemotherapy. Heart failure happens when the heart muscle has been weakened and can't pump blood as well as it should. Carvedilol may help lower the risk of cardiovascular complications.

Description

PRIMARY OBJECTIVES:
I. To determine the impact of a two-year course of low-dose carvedilol on surrogate echocardiographic indices of heart failure (HF) risk, including: Left ventricular (LV) posterior wall thickness-dimension ratio (LV T-D); LV systolic and diastolic function, and afterload; Natriuretic peptides, troponins, and galectin-3.
SECONDARY OBJECTIVES:
I. To establish safety and tolerability of this two-year course of low-dose carvedilol, assessing both objective measures (hepatic function) and patient reported outcomes.
II. To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year carvedilol intervention.
TERTIARY OBJECTIVES:
I. To evaluate the long-term efficacy of carvedilol in preventing cardiomyopathy and/or heart failure in high-risk childhood cancer survivors.
OUTLINE: This is a dose-escalation study. Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive low-dose carvedilol orally (PO) once daily (QD) or twice daily (BID) for 24 months.
ARM II: Patients receive placebo PO QD or BID for 24 months.
After completion of study treatment, patients are followed up for 3 years.

Eligibility

Inclusion Criteria:
- Males must weigh >55 Kg
- Females must weigh >50 Kg
- Patient must have had a cancer diagnosis < 21 years of age, irrespective of current age
- Patient must have a lifetime cumulative anthracycline dose: >= 300 mg/m^2 DOXOrubicin equivalent without the protection of dexrazoxane (zinecard) therapy
- Patient must have completed cancer treatment >= 2 years prior to study enrollment
Exclusion Criteria:
- Receiving treatment for cardiomyopathy or heart failure
- Ejection fraction of < 50% by radionuclide angiogram or echocardiogram
- Shortening fraction of < 25% by echocardiogram
- Uncorrected primary obstructive or severe regurgitative valvular disease:
- Nondilated (restrictive); or
- Hypertrophic cardiomyopathy; or
- Significant systemic ventricular outflow obstruction
- Sustained or symptomatic ventricular dysrhythmias uncontrolled with drug therapy or implantable device
- Significant conduction defects (i.e. second or third degree atrioventricular block or sick sinus syndrome)
- Bradycardia: heart rate < 50 beats per minute (BPM)
- Use of an investigational drug or beta adrenergic blockers, including metoprolol, sotalol, within 30 days of enrollment
- History of drug sensitivity or allergic reaction to alpha or beta-blockers
- Low resting systolic blood pressure: < 90 mmHg
- Use of any other blood pressure lowering medication for treatment of hypertension within 30 days of enrollment except calcium channel blockers and diuretics
- History or current clinical evidence of moderate-to-severe obstructive pulmonary disease or reactive airway diseases (i.e. asthma) requiring therapy
- Significant hepatic (serum aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] > 3 time upper limit of institutional normal)
- Gastrointestinal, or biliary disorders that could impair absorption, metabolism, or excretion of orally administered medications
- Endocrine disorders (such as primary aldosteronism, pheochromocytoma, hyper- or hypothyroidism) not controlled with medication
- Insulin dependent diabetes mellitus
- Anemia (hematocrit < 28%)
- Use of select cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) inhibitor or inducer medications
- Inability to swallow pills
- Female patients who are pregnant are not eligible; women of childbearing potential require a negative pregnancy test prior to starting study drug
- Lactating females are not eligible unless they have agreed to not breastfeed their infants
- Sexually active patients of reproductive potential are not eligible unless they agree to use an effective contraceptive method during study and for 2 months after stopping the study drug; abstinence is an acceptable method of birth control
- All patients and/or their parents or legal guardians must sign a written informed consent
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met