Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Congestive Heart Failure (PREVENT-CHF): A Phase IIB Randomized Placebo-Controlled Trial
Study Details
Study Description
Brief Summary
This randomized phase II trial studies the side effects and how well low-dose carvedilol works in preventing congestive heart failure (CHF) in younger cancer survivors exposed to high dose anthracyclines for management of childhood cancer. Carvedilol may help lower the risk of cardiovascular complications
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
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To determine the impact of a two-year course of low-dose carvedilol on surrogate echocardiographic indices of CHF risk, including: left ventricular (LV) posterior wall thickness-dimension ratio (LV T-D); LV systolic and diastolic function, and afterload; natriuretic peptides, troponins, and galactin-3.
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To establish safety and tolerability of this two-year course of low-dose carvedilol, assessing both objective measures (hepatic function) and patients reported outcomes.
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To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year carvedilol intervention.
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As an exploratory goal, to examine the relationship between carvedilol and clinical measures of efficacy such as prevention of CHF.
SECONDARY OBJECTIVES:
- 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 (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 5 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm I (beta-adrenergic/alpha-1 adrenergic blocker) Patients receive low-dose carvedilol PO QD or BID for 24 months. |
Drug: carvedilol
Given PO
Other Names:
Other: pharmacogenomic studies
Correlative studies
Other Names:
Other: laboratory biomarker analysis
Correlative studies
Procedure: quality-of-life assessment
Ancillary studies
Other Names:
Genetic: polymorphism analysis
Correlative studies
Genetic: microarray analysis
Correlative studies
Other Names:
Genetic: polymerase chain reaction
Correlative studies
Other Names:
Other: enzyme-linked immunosorbent assay
Correlative studies
Other Names:
Other: questionnaire administration
Ancillary studies
|
| Placebo Comparator: Arm II (placebo) Patients receive placebo PO QD or BID for 24 months. |
Other: placebo
Given PO
Other Names:
Other: pharmacogenomic studies
Correlative studies
Other Names:
Other: laboratory biomarker analysis
Correlative studies
Procedure: quality-of-life assessment
Ancillary studies
Other Names:
Genetic: polymorphism analysis
Correlative studies
Genetic: microarray analysis
Correlative studies
Other Names:
Genetic: polymerase chain reaction
Correlative studies
Other Names:
Other: enzyme-linked immunosorbent assay
Correlative studies
Other Names:
Other: questionnaire administration
Ancillary studies
|
Outcome Measures
Primary Outcome Measures
- LV thickness-dimension ratio (LV T-D), reported in terms of LV posterior wall dimension in systole and LV dimension based on the internal diameter in diastole [Up to 24 months]
Z-scores appropriately transformed to normality as necessary. The analysis will be conducted using the linear mixed-effects model approach for normally distributed data, to account for correlation among repeated measurements within individuals. This may be done using the generalized estimating equation (GEE) approach without the random effects or by the restricted maximum likelihood estimation (REML) approach with random effects. Various covariance structures will be assumed, including the unstructured, compound symmetry, and autoregressive lag-1 correlation. Implemented using GENMOD & MIXED.
Secondary Outcome Measures
- Echocardiographic efficacy measures, including afterload and systolic and diastolic measurements [Up to 24 months]
Evaluated in the manner described for primary outcome based on testing the significance of the interaction of time by group indicator variables. The distribution of continuous variables will be examined graphically and appropriate transformations made before applying analytical methods based on normal assumption.
- Blood biomarkers of myocardial remodeling and CHF risk, including cardiac troponins (cTn), blood natriuretic peptide (BNP), and galectin-3 [Up to 24 months]
Treated as continuous measures. The linear mixed effects model for between group comparisons of measures from the 5 time points will be applied. The unstructured mean model and linear in time model will be employed.
- Grade 2-4 toxicities, assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [Up to 24 months]
The number of grade 2-4 toxicities observed will be tabulated by treatment arm. Differences by treatment arm will be evaluated using Fisher exact tests.
- Frequency of individuals with elevated liver function measurements (bilirubin, AST, ALT) [Up to 24 months]
Compared between treatment groups using an exact test on 2 x 2 tables, stratified on CYP2D6. Logistic regression analysis will also be used to compare the trends in liver function levels between the treatment groups. Procs MIXED and GLIMMIX will be used for longitudinal analysis of normally and non-normally distributed data, respectively. Proc GENMOD will also be used for normally and non-normally distributed data.
- Subjective safety and tolerability measures, including treatment adherence as measured by pill counts and patient reported symptoms [Up to 24 months]
Voluntary withdrawals will be examined at the end of the study by comparing the percent of withdrawals between the treatment groups using a chi-square test or Fisher's exact test. Patient reported symptoms will be scored as a 5-point Likert-type scale in response to questions on how much patients are bothered by certain symptoms. The responses will be treated as normally distributed, as ordinal or dichotomized variable, and the linear mixed effects model or generalized linear mixed effects model will be applied to compare changes between treatment groups.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Cancer diagnosis prior to 22 years of age, irrespective of current age
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Lifetime cumulative anthracycline dose: >= 300 mg/m^2 without the protection of dexrazoxane (Zinecard) therapy
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Time from completion of cancer treatment to study entry: >= 2 years
Exclusion Criteria:
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Receiving treatment for cardiomyopathy or congestive heart failure
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Resting ejection fraction < 50% or fractional shortening < 25%
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Uncorrected primary obstructive or severe regurgitative valvular disease, nondilated (restrictive) or hypertrophic cardiomyopathy, or significant systemic ventricular outflow obstruction
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Low resting systolic blood pressure: < 90 mm hemoglobin (Hg)
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Bradycardia: heart rate < 50 beats per minute (BPM)
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Sustained or symptomatic ventricular dysrhythmias uncontrolled with drug therapy or implantable device; significant conduction defects (i.e.: second or third degree atrio-ventricular block or sick sinus syndrome)
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History or current clinical evidence of moderate -to-severe obstructive pulmonary disease or reactive airway diseases (i.e.: asthma) requiring therapy
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Significant hepatic (serum aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] > 3 time upper limit of normal institutional normal), gastrointestinal, or biliary disorders that could impair absorption, metabolism, or excretion of orally administered medications
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Endocrine disorders such as primary aldosteronism, pheochromocytoma, hyper- or hypothyroidism not controlled with medication, or insulin dependent diabetes mellitus
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Females of child bearing potential who are pregnant, lactating, or sexually active and not taking adequate contraceptive precautions (i.e.: intrauterine device [IUD] or oral contraceptives for 3 months prior to entry into the study)
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History of drug sensitivity or allergic reaction to alpha- or beta-blockers
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Anemia (hematocrit < 28%)
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Use of an investigational drug or beta adrenergic blockers, including metoprolol, sotalol, within 30 days of randomization
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Use of select cytochrome P450 2D6 (CYP2D6) inhibitor medications
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Inability to swallow pills
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Unwillingness or inability to cooperate, or, for the parents or guardians of minors, to give consent, or for the child to give assent, or any condition of sufficient severity to impair cooperation with the study
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Use of any other blood pressure lowering medication for treatment of hypertension, within 30 days of randomization
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope Medical Center | Duarte | California | United States | 91010 |
| 2 | University of Michigan, C.S. Mott Children's Hospital | Ann Arbor | Michigan | United States | 48109 |
| 3 | St. Jude Childrens Research Hospital | Memphis | Tennessee | United States | 38105 |
| 4 | University Health Network-Princess Margaret Hospital | Toronto | Ontario | Canada | M5G 2M9 |
Sponsors and Collaborators
- City of Hope Medical Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Saro Armenian, DO, MPH, City of Hope Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 11018
- NCI-2011-00717
- K12CA001727