search
Back to results

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

Primary Purpose

Cancer Survivor

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
carvedilol
placebo
pharmacogenomic studies
laboratory biomarker analysis
quality-of-life assessment
polymorphism analysis
microarray analysis
polymerase chain reaction
enzyme-linked immunosorbent assay
questionnaire administration
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Cancer Survivor focused on measuring childhood cancer survivor, CHF, risk of congestive heart failure

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • City of Hope Medical Center
  • University of Michigan, C.S. Mott Children's Hospital
  • St. Jude Childrens Research Hospital
  • University Health Network-Princess Margaret Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm I (beta-adrenergic/alpha-1 adrenergic blocker)

Arm II (placebo)

Arm Description

Patients receive low-dose carvedilol PO QD or BID for 24 months.

Patients receive placebo PO QD or BID for 24 months.

Outcomes

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
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
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
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
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)
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
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.

Full Information

First Posted
May 2, 2011
Last Updated
March 29, 2022
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
search

1. Study Identification

Unique Protocol Identification Number
NCT01347970
Brief 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
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
May 2012 (undefined)
Primary Completion Date
June 1, 2022 (Anticipated)
Study Completion Date
December 1, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. 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
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cancer Survivor
Keywords
childhood cancer survivor, CHF, risk of congestive heart failure

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
250 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm I (beta-adrenergic/alpha-1 adrenergic blocker)
Arm Type
Experimental
Arm Description
Patients receive low-dose carvedilol PO QD or BID for 24 months.
Arm Title
Arm II (placebo)
Arm Type
Placebo Comparator
Arm Description
Patients receive placebo PO QD or BID for 24 months.
Intervention Type
Drug
Intervention Name(s)
carvedilol
Other Intervention Name(s)
Coreg
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
placebo
Other Intervention Name(s)
PLCB
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
pharmacogenomic studies
Other Intervention Name(s)
Pharmacogenomic Study
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Procedure
Intervention Name(s)
quality-of-life assessment
Other Intervention Name(s)
quality of life assessment
Intervention Description
Ancillary studies
Intervention Type
Genetic
Intervention Name(s)
polymorphism analysis
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
microarray analysis
Other Intervention Name(s)
gene expression profiling
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
polymerase chain reaction
Other Intervention Name(s)
PCR
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
enzyme-linked immunosorbent assay
Other Intervention Name(s)
ELISA
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
questionnaire administration
Intervention Description
Ancillary studies
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Up to 24 months
Secondary Outcome Measure Information:
Title
Echocardiographic efficacy measures, including afterload and systolic and diastolic measurements
Description
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.
Time Frame
Up to 24 months
Title
Blood biomarkers of myocardial remodeling and CHF risk, including cardiac troponins (cTn), blood natriuretic peptide (BNP), and galectin-3
Description
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.
Time Frame
Up to 24 months
Title
Grade 2-4 toxicities, assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Description
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.
Time Frame
Up to 24 months
Title
Frequency of individuals with elevated liver function measurements (bilirubin, AST, ALT)
Description
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.
Time Frame
Up to 24 months
Title
Subjective safety and tolerability measures, including treatment adherence as measured by pill counts and patient reported symptoms
Description
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.
Time Frame
Up to 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Saro Armenian, DO, MPH
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
University of Michigan, C.S. Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
St. Jude Childrens Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
University Health Network-Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada

12. IPD Sharing Statement

Learn more about this trial

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

We'll reach out to this number within 24 hrs