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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02717507




Registration number
NCT02717507
Ethics application status
Date submitted
9/03/2016
Date registered
23/03/2016
Date last updated
10/07/2020

Titles & IDs
Public title
Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors
Scientific 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
Secondary ID [1] 0 0
NCI-2016-00232
Secondary ID [2] 0 0
ALTE1621
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Neoplasm 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Carvedilol
Other interventions - Laboratory Biomarker Analysis
Other interventions - Pharmacogenomic Study
Other interventions - Pharmacological Study
Other interventions - Placebo Administration
Other interventions - Quality-of-Life Assessment
Other interventions - Questionnaire Administration

Experimental: Arm I (carvedilol) - Patients receive low-dose carvedilol PO QD or BID for 24 months.

Placebo Comparator: Arm II (placebo) - Patients receive placebo PO QD or BID for 24 months.


Treatment: Drugs: Carvedilol
Given PO

Other interventions: Laboratory Biomarker Analysis
Correlative studies

Other interventions: Pharmacogenomic Study
Correlative studies

Other interventions: Pharmacological Study
Correlative studies

Other interventions: Placebo Administration
Given PO

Other interventions: Quality-of-Life Assessment
Ancillary studies

Other interventions: Questionnaire Administration
Ancillary studies

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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 - 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.
Timepoint [1] 0 0
Up to 24 months
Secondary outcome [1] 0 0
Afterload measurements - 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.
Timepoint [1] 0 0
Up to 24 months
Secondary outcome [2] 0 0
Systolic measurements - 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.
Timepoint [2] 0 0
Up to 24 months
Secondary outcome [3] 0 0
Diastolic measurements - 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.
Timepoint [3] 0 0
Up to 24 months
Secondary outcome [4] 0 0
Blood natriuretic peptide (BNP) level - 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.
Timepoint [4] 0 0
Up to 24 months
Secondary outcome [5] 0 0
Cardiac troponins (cTnT and cTnI) level - 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.
Timepoint [5] 0 0
Up to 24 months
Secondary outcome [6] 0 0
Galectin-3 level - 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.
Timepoint [6] 0 0
Up to 24 months
Secondary outcome [7] 0 0
Grade 2-4 adverse events - 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.
Timepoint [7] 0 0
Up to 24 months
Secondary outcome [8] 0 0
Frequency of individuals with elevated liver function measurements (bilirubin, aspartate aminotransferase, alanine aminotransferase) - 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.
Timepoint [8] 0 0
Up to 24 months
Secondary outcome [9] 0 0
Treatment adherence as measured by pill counts - 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.
Timepoint [9] 0 0
Up to 24 months
Secondary outcome [10] 0 0
Patient reported symptoms - 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.
Timepoint [10] 0 0
Up to 24 months

Eligibility
Key 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
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Suspended
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 0 0
Princess Margaret Hospital for Children - Perth
Recruitment hospital [2] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
6008 - Perth
Recruitment postcode(s) [2] 0 0
6009 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
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Arizona
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Arkansas
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California
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Colorado
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Connecticut
Country [7] 0 0
United States of America
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Delaware
Country [8] 0 0
United States of America
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District of Columbia
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Florida
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United States of America
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Georgia
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Hawaii
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Illinois
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Indiana
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Iowa
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Kentucky
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Louisiana
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Maryland
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Michigan
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Minnesota
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Mississippi
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Missouri
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Nebraska
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Nevada
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New Jersey
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New York
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North Carolina
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Ohio
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Oklahoma
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Oregon
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Pennsylvania
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South Carolina
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Tennessee
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Texas
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Virginia
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Washington
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Canada
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Nova Scotia
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New Zealand
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Auckland
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New Zealand
State/province [38] 0 0
Christchurch

Funding & Sponsors
Primary sponsor type
Other
Name
Children's Oncology Group
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Cancer Institute (NCI)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This randomized 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.
Trial website
https://clinicaltrials.gov/show/NCT02717507
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Saro H Armenian
Address 0 0
Children's Oncology Group
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02717507