Clinical trial NCT02717507: Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hematopoietic and Lymphoid Cell Neoplasm
Malignant Solid Neoplasm
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2016-03-23
Enrollment: 196
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility 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

Primary outcomes:
measure: Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz)
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Secondary outcomes:
measure: Average Left Ventricular End-systolic Wall Stress
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Left Ventricular End-systolic Dimension
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Left Ventricular End-systolic Volume
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Left Ventricular End-diastolic Dimension
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Left Ventricular End-diastolic Volume
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Left Ventricular Mass
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Fractional Shortening
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Ejection Fraction
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Peak Early Atrial Divided by Peak Late Atrial Velocities
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average N-terminal Pro B-type Natriuretic Peptide
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Cardiac N-terminal Pro B-type Natriuretic Peptide
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Cardiac Troponin I
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Galectin-3
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Proportion of Patients With Reportable Adverse Events as Described in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).
timeFrame: From baseline to month 24 since baseline
measure: Average Bilirubin
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Aspartate Aminotransferase
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Average Alanine Aminotransferase
timeFrame: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
measure: Proportion of Participants With Average Adherence > 90%
timeFrame: Average adherence across 6 months, 12 months, 18 months, 24 months after treatment initiation are calculated.
measure: Proportion of Patients Who Responded "Moderately", "Quite a Bit", or "Extremely" to the Question of How Bothersome the Listed Symptom Was at Any Post-day 0 Assessment Time Point.
timeFrame: Responses at days 14 to 730 were combined
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Downey
country: United States
facility: Kaiser Permanente Downey Medical Center
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Long Beach
country: United States
facility: Miller Children's and Women's Hospital Long Beach
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Oakland
country: United States
facility: Kaiser Permanente-Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: Torrance
country: United States
facility: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Fort Myers
country: United States
facility: Golisano Children's Hospital of Southwest Florida
state: Florida
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic-Jacksonville
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: Pensacola
country: United States
facility: Nemours Children's Clinic - Pensacola
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Tampa
country: United States
facility: Saint Joseph's Hospital/Children's Hospital-Tampa
state: Florida
city: West Palm Beach
country: United States
facility: Saint Mary's Medical Center
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Arthur M Blank Hospital
state: Georgia
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Oak Lawn
country: United States
facility: Advocate Children's Hospital-Oak Lawn
state: Illinois
city: Park Ridge
country: United States
facility: Advocate Children's Hospital-Park Ridge
state: Illinois
city: Indianapolis
country: United States
facility: Ascension Saint Vincent Indianapolis Hospital
state: Indiana
city: Des Moines
country: United States
facility: Blank Children's Hospital
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Louisville
country: United States
facility: Norton Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Children's Hospital New Orleans
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Medical Center Jefferson
state: Louisiana
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota - Minneapolis
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Medical Center
state: Missouri
city: Omaha
country: United States
facility: Children's Hospital and Medical Center of Omaha
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: University Medical Center of Southern Nevada
state: Nevada
city: Las Vegas
country: United States
facility: Sunrise Hospital and Medical Center
state: Nevada
city: Las Vegas
country: United States
facility: Alliance for Childhood Diseases/Cure 4 the Kids Foundation
state: Nevada
city: Las Vegas
country: United States
facility: Summerlin Hospital Medical Center
state: Nevada
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Paterson
country: United States
facility: Saint Joseph's Regional Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Mineola
country: United States
facility: NYU Langone Hospital - Long Island
state: New York
city: New Hyde Park
country: United States
facility: The Steven and Alexandra Cohen Children's Medical Center of New York
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Asheville
country: United States
facility: Mission Hospital
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Legacy Emanuel Children's Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: BI-LO Charities Children's Cancer Center
state: South Carolina
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Austin
country: United States
facility: Dell Children's Medical Center of Central Texas
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: El Paso
country: United States
facility: El Paso Children's Hospital
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center and Children's Hospital
state: Washington
city: Tacoma
country: United States
facility: Mary Bridge Children's Hospital and Health Center
state: Washington
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Perth
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Grafton
country: New Zealand
facility: Starship Children's Hospital
state: Auckland
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
Study officials:
affiliation: Children's Oncology Group
name: Saro H Armenian
role: PRINCIPAL_INVESTIGATOR
References:
citation: Armenian SH, Hudson MM, Chen MH, Colan SD, Lindenfeld L, Mills G, Siyahian A, Gelehrter S, Dang H, Hein W, Green DM, Robison LL, Wong FL, Douglas PS, Bhatia S. Rationale and design of the Children's Oncology Group (COG) study ALTE1621: a randomized, placebo-controlled trial to determine if low-dose carvedilol can prevent anthracycline-related left ventricular remodeling in childhood cancer survivors at high risk for developing heart failure. BMC Cardiovasc Disord. 2016 Oct 4;16(1):187. doi: 10.1186/s12872-016-0364-6.