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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT01347970
Other study ID # 11018
Secondary ID NCI-2011-00717K1
Status Active, not recruiting
Phase Phase 2
First received
Last updated
Start date May 2012
Est. completion date December 1, 2022

Study information

Verified date March 2022
Source City of Hope Medical Center
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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


Description:

PRIMARY OBJECTIVES: I. 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. II. To establish safety and tolerability of this two-year course of low-dose carvedilol, assessing both objective measures (hepatic function) and patients reported outcomes. III. To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year carvedilol intervention. IV. As an exploratory goal, to examine the relationship between carvedilol and clinical measures of efficacy such as prevention of CHF. SECONDARY OBJECTIVES: I. 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.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 250
Est. completion date December 1, 2022
Est. primary completion date June 1, 2022
Accepts healthy volunteers No
Gender All
Age group 16 Years and older
Eligibility Inclusion Criteria: - Cancer diagnosis prior to 22 years of age, irrespective of current age - Lifetime cumulative anthracycline dose: >= 300 mg/m^2 without the protection of dexrazoxane (Zinecard) therapy - Time from completion of cancer treatment to study entry: >= 2 years Exclusion Criteria: - Receiving treatment for cardiomyopathy or congestive heart failure - Resting ejection fraction < 50% or fractional shortening < 25% - Uncorrected primary obstructive or severe regurgitative valvular disease, nondilated (restrictive) or hypertrophic cardiomyopathy, or significant systemic ventricular outflow obstruction - Low resting systolic blood pressure: < 90 mm hemoglobin (Hg) - Bradycardia: heart rate < 50 beats per minute (BPM) - 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) - 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 normal 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, or insulin dependent diabetes mellitus - 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) - History of drug sensitivity or allergic reaction to alpha- or beta-blockers - Anemia (hematocrit < 28%) - Use of an investigational drug or beta adrenergic blockers, including metoprolol, sotalol, within 30 days of randomization - Use of select cytochrome P450 2D6 (CYP2D6) inhibitor medications - Inability to swallow pills - 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 - Use of any other blood pressure lowering medication for treatment of hypertension, within 30 days of randomization

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
carvedilol
Given PO
Other:
placebo
Given PO
pharmacogenomic studies
Correlative studies
laboratory biomarker analysis
Correlative studies
Procedure:
quality-of-life assessment
Ancillary studies
Genetic:
polymorphism analysis
Correlative studies
microarray analysis
Correlative studies
polymerase chain reaction
Correlative studies
Other:
enzyme-linked immunosorbent assay
Correlative studies
questionnaire administration
Ancillary studies

Locations

Country Name City State
Canada University Health Network-Princess Margaret Hospital Toronto Ontario
United States University of Michigan, C.S. Mott Children's Hospital Ann Arbor Michigan
United States City of Hope Medical Center Duarte California
United States St. Jude Childrens Research Hospital Memphis Tennessee

Sponsors (2)

Lead Sponsor Collaborator
City of Hope Medical Center National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 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. Up to 24 months
Secondary Echocardiographic efficacy measures, including afterload and systolic and diastolic measurements 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. Up to 24 months
Secondary Blood biomarkers of myocardial remodeling and CHF risk, including cardiac troponins (cTn), blood natriuretic peptide (BNP), and galectin-3 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. Up to 24 months
Secondary Grade 2-4 toxicities, assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 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. Up to 24 months
Secondary Frequency of individuals with elevated liver function measurements (bilirubin, AST, ALT) 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. Up to 24 months
Secondary Subjective safety and tolerability measures, including treatment adherence as measured by pill counts and patient reported symptoms 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. Up to 24 months
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