Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Heart Failure (PREVENT-HF): A Phase 2b Randomized Placebo-Controlled (Carvedilol) Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 196
- 试验地点
- 91
- 主要终点
- Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Arm II (placebo)
Patients receive placebo PO QD or BID for 24 months.
干预措施: Pharmacological Study (Other)
Arm I (carvedilol)
Patients receive low-dose carvedilol PO QD or BID for 24 months.
干预措施: Carvedilol (Drug)
Arm I (carvedilol)
Patients receive low-dose carvedilol PO QD or BID for 24 months.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (carvedilol)
Patients receive low-dose carvedilol PO QD or BID for 24 months.
干预措施: Pharmacogenomic Study (Other)
Arm I (carvedilol)
Patients receive low-dose carvedilol PO QD or BID for 24 months.
干预措施: Pharmacological Study (Other)
Arm I (carvedilol)
Patients receive low-dose carvedilol PO QD or BID for 24 months.
干预措施: Quality-of-Life Assessment (Other)
Arm I (carvedilol)
Patients receive low-dose carvedilol PO QD or BID for 24 months.
干预措施: Questionnaire Administration (Other)
Arm II (placebo)
Patients receive placebo PO QD or BID for 24 months.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (placebo)
Patients receive placebo PO QD or BID for 24 months.
干预措施: Pharmacogenomic Study (Other)
Arm II (placebo)
Patients receive placebo PO QD or BID for 24 months.
干预措施: Placebo Administration (Other)
Arm II (placebo)
Patients receive placebo PO QD or BID for 24 months.
干预措施: Quality-of-Life Assessment (Other)
Arm II (placebo)
Patients receive placebo PO QD or BID for 24 months.
干预措施: Questionnaire Administration (Other)
结局指标
主要结局
Average Left-Ventricular Wall Thickness-Dimension Ratio Z-score (LVWT/Dz)
时间窗: Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation
Z-score of the ratio of left ventricular (LV) posterior wall dimension of systole to internal LV dimension in diastole, calculated for each subject by subtracting the reference healthy population mean, then dividing by the standard deviation. The Z-score indicates the number of standard deviations away from the mean of the reference population. Negative Z- score indicates worse outcome. The mean is reported by arm at each timepoint with corresponding standard errors.
次要结局
- Average Alanine Aminotransferase(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Left Ventricular End-systolic Wall Stress(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Left Ventricular Mass(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Fractional Shortening(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Ejection Fraction(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Peak Early Atrial Divided by Peak Late Atrial Velocities(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Cardiac N-terminal Pro B-type Natriuretic Peptide(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Left Ventricular End-systolic Dimension(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Left Ventricular End-systolic Volume(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Left Ventricular End-diastolic Dimension(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Left Ventricular End-diastolic Volume(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average N-terminal Pro B-type Natriuretic Peptide(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Galectin-3(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Cardiac Troponin I(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Average Aspartate Aminotransferase(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- Proportion of Participants With Average Adherence > 90%(Average adherence across 6 months, 12 months, 18 months, 24 months after treatment initiation are calculated.)
- Proportion of Patients With Reportable Adverse Events as Described in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).(From baseline to month 24 since baseline)
- Average Bilirubin(Baseline before treatment, 6 months, 12 months, 18 months, 24 months after treatment initiation)
- 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.(Responses at days 14 to 730 were combined)