Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Congestive Heart Failure (PREVENT-CHF): A Phase IIB Randomized Placebo-Controlled Trial

Cancer Survivor Clinical Trial

Official title:

Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Congestive Heart Failure (PREVENT-CHF): A Phase IIB Randomized Placebo-Controlled Trial

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
• 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
• 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

Related Conditions & MeSH terms

• Cancer Survivor
• Heart Failure
• Ventricular Remodeling

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