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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT01347970
First received: May 2, 2011
Last updated: August 6, 2014
Last verified: August 2014
  Purpose

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 Intervention Phase
Cancer Survivor
Drug: carvedilol
Other: placebo
Other: pharmacogenomic studies
Other: laboratory biomarker analysis
Procedure: quality-of-life assessment
Genetic: polymorphism analysis
Genetic: microarray analysis
Genetic: polymerase chain reaction
Other: enzyme-linked immunosorbent assay
Other: questionnaire administration
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Supportive Care
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

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • LV thickness-dimension ration (LV T-D), reported in terms of LV posterior wall dimension in systole and LV dimension based on the internal diameter in diastole [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 24 months ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 250
Study Start Date: May 2012
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Coreg
Other: pharmacogenomic studies
Correlative studies
Other Name: Pharmacogenomic Study
Other: laboratory biomarker analysis
Correlative studies
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Genetic: polymorphism analysis
Correlative studies
Genetic: microarray analysis
Correlative studies
Other Name: gene expression profiling
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Other: enzyme-linked immunosorbent assay
Correlative studies
Other Name: ELISA
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 Name: PLCB
Other: pharmacogenomic studies
Correlative studies
Other Name: Pharmacogenomic Study
Other: laboratory biomarker analysis
Correlative studies
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Genetic: polymorphism analysis
Correlative studies
Genetic: microarray analysis
Correlative studies
Other Name: gene expression profiling
Genetic: polymerase chain reaction
Correlative studies
Other Name: PCR
Other: enzyme-linked immunosorbent assay
Correlative studies
Other Name: ELISA
Other: questionnaire administration
Ancillary studies

Detailed Description:

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.

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 annually.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01347970

Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Saro H. Armenian, DO, MPH    626-471-7320    sarmenian@coh.org   
Principal Investigator: Saro H. Armenian, DO, MPH         
United States, Michigan
University of Michigan, C.S. Mott Children's Hospital Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Sarah Gelehrter, MD    734-936-4000    sgelehrt@med.umich.edu   
Principal Investigator: Sarah Gelehrter, MD         
United States, Tennessee
St. Jude Childrens Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Melissa M. Hudson, MD    901-595-4644    melissa.hudson@stjude.org   
Principal Investigator: Melissa M. Hudson, MD         
Canada, Ontario
University Health Network-Princess Margaret Hospital Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: David Hodgson, MD    416-946-2919    david.hodgson@rmp.uhn.on.ca   
Principal Investigator: David Hodgson, MD         
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Saro Armenian, DO, MPH City of Hope Medical Center
  More Information

No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT01347970     History of Changes
Other Study ID Numbers: 11018, NCI-2011-00717, K12CA001727
Study First Received: May 2, 2011
Last Updated: August 6, 2014
Health Authority: United States: Federal Government
United States: Institutional Review Board

Keywords provided by City of Hope Medical Center:
childhood cancer survivor
CHF
risk of congestive heart failure

Additional relevant MeSH terms:
Heart Failure
Ventricular Remodeling
Cardiovascular Diseases
Heart Diseases
Pathological Conditions, Anatomical
Carvedilol
Adrenergic Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic beta-Antagonists
Antihypertensive Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on October 30, 2014