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Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02717507
Recruitment Status : Active, not recruiting
First Posted : March 23, 2016
Last Update Posted : October 3, 2022
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Study Description
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Brief Summary:
This phase IIb trial studies how well low-dose carvedilol works in preventing heart failure in cancer survivors exposed to high dose anthracyclines for management of childhood cancer. Patients who received high-dose anthracycline chemotherapy are at a much greater risk for developing heart failure compared to survivors who didn't get any anthracycline chemotherapy. Heart failure happens when the heart muscle has been weakened and can't pump blood as well as it should. Carvedilol may help lower the risk of cardiovascular complications.

Condition or disease Intervention/treatment Phase
Hematopoietic and Lymphoid Cell Neoplasm Malignant Solid Neoplasm Drug: Carvedilol Other: Laboratory Biomarker Analysis Other: Pharmacogenomic Study Other: Pharmacological Study Other: Placebo Administration Other: Quality-of-Life Assessment Other: Questionnaire Administration Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To determine the impact of a two-year course of low-dose carvedilol on surrogate echocardiographic indices of heart failure (HF) risk, including: Left ventricular (LV) posterior wall thickness-dimension ratio (LV T-D); LV systolic and diastolic function, and afterload; Natriuretic peptides, troponins, and galectin-3.

SECONDARY OBJECTIVES:

I. To establish safety and tolerability of this two-year course of low-dose carvedilol, assessing both objective measures (hepatic function) and patient reported outcomes.

II. To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year carvedilol intervention.

EXPLORATORY OBJECTIVE:

I. To 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 daily (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 3 years.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 182 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Heart Failure (PREVENT-HF): A Phase 2b Randomized Placebo-Controlled (Carvedilol) Trial
Actual Study Start Date : April 4, 2016
Actual Primary Completion Date : June 30, 2022
Estimated Study Completion Date : September 30, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Carvedilol

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm I (carvedilol)
Patients receive low-dose carvedilol PO QD or BID for 24 months.
 Drug: Carvedilol
Given PO
Other Name: Coreg

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacogenomic Study
Correlative studies
Other Name: PHARMACOGENOMIC

Other: Pharmacological Study
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies
Placebo Comparator: Arm II (placebo)
Patients receive placebo PO QD or BID for 24 months.
 Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacogenomic Study
Correlative studies
Other Name: PHARMACOGENOMIC

Other: Pharmacological Study
Correlative studies

Other: Placebo Administration
Given PO

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies


Outcome Measures
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Primary Outcome Measures :
  1. Left ventricular (LV) thickness-dimension ratio (LVT-D) derived from echocardiogram, 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 ]
    Z-scores appropriately transformed to normality as necessary. The analysis will be conducted accounting for correlation among repeated measurements within individuals. This may be done using the generalized estimating equation (GEE) approach or by linear mixed effects (LME) model with random effects. Various covariance structures will be assumed, including the unstructured, compound symmetry, and autoregressive lag-1 correlation. GEE and LME models will be implemented using GENMOD and MIXED procedures using the Statistical Analysis System (SAS) software. LV T-D z-scores will be modeled as a linear function of time. A treatment group by time interaction will be included and tested to assess the intervention effects.


Secondary Outcome Measures :
  1. Afterload measurements [ Time Frame: Up to 24 months ]
    Evaluated in the manner described for primary outcome based on testing the significance of the interaction of time by group variables. The distribution of continuous variables will be examined graphically and appropriate transformations made before applying analytical methods based on normal assumption.

  2. Systolic measurements [ Time Frame: Up to 24 months ]
    Evaluated in the manner described for primary outcome based on testing the significance of the interaction of time by group variables. The distribution of continuous variables will be examined graphically and appropriate transformations made before applying analytical methods based on normal assumption.

  3. Diastolic measurements [ Time Frame: Up to 24 months ]
    Evaluated in the manner described for primary outcome based on testing the significance of the interaction of time by group variables. The distribution of continuous variables will be examined graphically and appropriate transformations made before applying analytical methods based on normal assumption.

  4. Blood natriuretic peptide (BNP) level [ Time Frame: 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.

  5. Cardiac troponins (cTnT and cTnI) level [ Time Frame: 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.

  6. Galectin-3 level [ Time Frame: 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.

  7. Grade 2-4 adverse events [ Time Frame: Up to 24 months ]
    Will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 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.

  8. Frequency of individuals with elevated liver function measurements (bilirubin, aspartate aminotransferase, alanine aminotransferase) [ Time Frame: Up to 24 months ]
    Compared between treatment groups using an exact test on 2x2 tables, stratified on CYP2D6. Logistic regression analysis will also be used to compare the frequency of elevated liver function between treatments, adjusted for covariates. Linear mixed-effects model for normally distributed data 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.

  9. Treatment adherence as measured by pill counts [ Time Frame: 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.

  10. Patient reported symptoms [ Time Frame: Up to 24 months ]
    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
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Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males and females must weigh >= 40 Kg
  • Patient must have had a cancer diagnosis < 22 years of age, irrespective of current age

  • Patient must have a lifetime cumulative anthracycline dose of >= 250 mg/m^2 DOXOrubicin equivalent without the protection of dexrazoxane (Zinecard) therapy; the anthracycline dose threshold must be met as part of the treatment of a cancer that was diagnosed at < 22 years of age

    • Note: Institutional records (e.g., clinic note, treatment summary, chemotherapy roadmap) can be used to document lifetime receipt of anthracycline dose
  • Patient must have completed cancer treatment >= 2 years prior to study enrollment

Exclusion Criteria:

  • Receiving treatment for cardiomyopathy or heart failure

  • Ejection fraction of < 50% (by radionuclide angiogram or echocardiogram) or shortening fraction of < 25% (by echocardiogram)

    • Note: for instances where both are reported, and one is below the threshold, the site will have the option to re-measure it centrally at the core lab

  • Uncorrected primary obstructive or severe regurgitative valvular disease:

    • Nondilated (restrictive); or
    • Hypertrophic cardiomyopathy; or
    • Significant systemic ventricular outflow obstruction
  • 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)
  • Bradycardia: heart rate < 50 beats per minute (BPM)
  • Use of an investigational drug or beta adrenergic blockers, including metoprolol, sotalol, within 30 days of enrollment
  • History of drug sensitivity or allergic reaction to alpha or beta-blockers
  • Low resting systolic blood pressure: < 90 mmHg
  • Use of any other blood pressure lowering medication for treatment of hypertension within 30 days of enrollment except calcium channel blockers and diuretics
  • History or current clinical evidence of moderate-to-severe obstructive pulmonary disease or reactive airway diseases (i.e. asthma) requiring therapy
  • Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times upper limit of 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
  • Uncontrolled diabetes (controlled diabetes per the American Diabetes Association and International Diabetes Center's Glycemic Target Goals is hemoglobin A1C < 7%)
  • Anemia (hematocrit < 28%)
  • Currently using select CYP2D6 inhibitor or inducer medications
  • Inability to swallow pills
  • Female patients who are pregnant are not eligible; women of childbearing potential require a negative pregnancy test prior to starting study drug
  • Lactating females are not eligible unless they have agreed to not breastfeed their infants
  • Sexually active female patients of reproductive potential are not eligible unless they agree to use an effective contraceptive method during study and for 2 months after stopping the study drug; abstinence is an acceptable method of birth control
  • All patients and/or their parents or legal guardians must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02717507


Locations
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Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Saro H Armenian Children's Oncology Group
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT02717507    
Obsolete Identifiers: NCT01347970
Other Study ID Numbers: ALTE1621
NCI-2016-00232 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ALTE1621 ( Other Identifier: Children's Oncology Group )
COG-ALTE1621 ( Other Identifier: DCP )
ALTE1621 ( Other Identifier: CTEP )
R01CA196854 ( U.S. NIH Grant/Contract )
UG1CA189955 ( U.S. NIH Grant/Contract )
First Posted: March 23, 2016    Key Record Dates
Last Update Posted: October 3, 2022
Last Verified: August 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Neoplasms
Heart Failure
Heart Diseases
Cardiovascular Diseases
Carvedilol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
 Physiological Effects of Drugs
Antihypertensive Agents
Antioxidants
Protective Agents
Calcium Channel Blockers
Membrane Transport Modulators
Calcium-Regulating Hormones and Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists