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出境医 / 临床实验 / Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab (CCTGuide Pilot)

Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab (CCTGuide Pilot)

Study Description
Brief Summary:
Investigators will evaluate the safety, tolerability, and feasibility of a risk-guided cardioprotective treatment strategy with carvedilol, as compared to usual care, in breast cancer patients undergoing treatment with doxorubicin, trastuzumab, or the combination.

Condition or disease Intervention/treatment Phase
Cardiotoxicity Risk Factor, Cardiovascular Toxicity Due to Chemotherapy Breast Cancer Cardiomyopathies Heart Failure Drug: Carvedilol Phase 1

Detailed Description:
This is a single-center, randomized clinical trial that seeks to determine if a risk guided treatment strategy that initiates carvedilol in high risk breast cancer patients prior to doxorubicin and/or trastuzumab is safe, tolerable, and feasible. Subjects who are identified as having elevated CTX Risk by an internally validated clinical risk score (exceeding a pre-specified risk threshold) will be randomized to individually-dosed, open-label carvedilol or usual care. Investigators will use a stratified randomization according to trastuzumab therapy (yes/no) to ensure balance across treatment regimen. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: An internally validated CV risk score will be used to determine an individual patient's risk. Low risk patients will be observed and managed according to usual care. Elevated risk patients will be randomized to open label, individually dosed carvedilol for 1 year or usual care.
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: A Pilot Study of Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab
Actual Study Start Date : August 9, 2019
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : December 31, 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: Carvedilol

Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months.

Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.

 Drug: Carvedilol
Individually dosed carvedilol
Other Name: Coreg
No Intervention: Usual Care
Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Outcome Measures
Primary Outcome Measures :
  1. Left Ventricular Ejection Fraction (LVEF) [ Time Frame: up to 24 months ]
    LVEF derived from quantitative analyses of echocardiography-derived measurements of left ventricular volumes in diastole and systole.

  2. Treatment adherence as measured by pill count [ Time Frame: 12 months ]
    Rate of compliance with prescribed dose of carvedilol by pill count

  3. Adverse Events [ Time Frame: Up to 24 months ]
    Adverse Events will be assessed using the CTCAE v5.0. The number of Grade 2-5 toxicities observed will be tabulated by risk group and by treatment arm. Differences will be evaluated using Fisher exact tests.


Secondary Outcome Measures :
  1. Diastolic function (E/e') by echocardiogram [ Time Frame: up to 24 months ]
    The mitral valve inflow velocity divided by the average early diastolic tissue velocities of the mitral valve annulus (septal, lateral) measured by tissue Doppler echocardiography.

  2. Ventricular-arterial coupling measured by echocardiogram [ Time Frame: up to 24 months ]
    Defined by echocardiography-derived measures of end systolic elastance divided by effective arterial elastance

  3. Cardiac Strain measurements by echocardiogram [ Time Frame: up to 24 months ]
    Echocardiography-derived measures of longitudinal, circumferential, and radial strain.

  4. Frequency of individuals with clinical heart failure [ Time Frame: up to 24 months ]
    Frequency of clinical heart failure diagnosis

  5. High-sensitivity Troponin (hsTnT) level [ Time Frame: up to 24 months ]
    Change in the cardiac biomarker of injury hsTnT over time, defined as a continuous variable

  6. N-terminal pro B-type natriuetic peptide (NTproBNP) level [ Time Frame: up to 24 months ]
    Change in the cardiac biomarker of neurohormonal stress NT-proBNP over time, defined as a continuous variable


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Females
  • At least 18 years old
  • Diagnosed with Stage I-III breast cancer with treatment plan to include therapy with anthracyclines and/or trastuzumab in the adjuvant or neo-adjuvant setting
  • Study team is able to obtain all necessary information for calculating Cardiotoxicity Risk Score (including echocardiographic measurement of left ventricular ejection fraction)

Exclusion Criteria:

  • Pregnant or breast feeding. Due to unknown risks and potential harm to the unborn fetus a negative pregnancy test within 10 days prior to enrollment is required in women with child-bearing potential. Due to the potential nursing infant harm, women who are currently breast feeding are not eligible for this study.
  • Contraindication to carvedilol
  • Baseline systolic blood pressure < 90mmHg (if multiple blood pressures are available in the medical record within 1 month prior to screening, the average SBP will be considered)
  • Baseline heart rate < 55 bpm consistent with severe bradycardia (if multiple resting heart rates are available in the medical record within 1 month prior to screening, the average heart rate will be considered)
  • Allergy to carvedilol
  • History of bronchial asthma or related bronchospastic conditions
  • Known history of sick sinus syndrome
  • Severe hepatic impairment, defined as serum bilirubin > 3.0x ULN, AST or ALT > 5.0 ULN within 28 days of enrollment
  • Second- or third-degree AV block, as determined by electrocardiogram
  • Severe bradycardia (unless permanent pacemaker is in place)
  • Patients in cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy
  • Current use of: Bupropion (Wellbutrin), Fluoxetine (Prozac), Paroxetine (Paxil), Quinidine (Quinidex), Duloxetine (Cymbalta), Digoxin
  • Current treatment with beta blocker
  • Unable to provide consent
Contacts and Locations

Contacts
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Contact: Bonnie Ky, MD, MSCE 215-573-6606 bonnie.ky@uphs.upenn.edu

Locations
Layout table for location information
United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Bonnie Ky, MD, MSCE    855-216-0098    PennCancerTrials@emergingmed.com   
Sponsors and Collaborators
Abramson Cancer Center of the University of Pennsylvania
Investigators
Layout table for investigator information
Principal Investigator: Bonnie Ky, MD, MSCE Perelman School of Medicine at the University of Pennsylvania
Tracking Information
First Submitted Date  ICMJE March 22, 2019
First Posted Date  ICMJE July 17, 2019
Last Update Posted Date May 6, 2021
Actual Study Start Date  ICMJE August 9, 2019
Estimated Primary Completion Date June 30, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 16, 2019)
  • Left Ventricular Ejection Fraction (LVEF) [ Time Frame: up to 24 months ]
    LVEF derived from quantitative analyses of echocardiography-derived measurements of left ventricular volumes in diastole and systole.
  • Treatment adherence as measured by pill count [ Time Frame: 12 months ]
    Rate of compliance with prescribed dose of carvedilol by pill count
  • Adverse Events [ Time Frame: Up to 24 months ]
    Adverse Events will be assessed using the CTCAE v5.0. The number of Grade 2-5 toxicities observed will be tabulated by risk group and by treatment arm. Differences will be evaluated using Fisher exact tests.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 16, 2019)
  • Diastolic function (E/e') by echocardiogram [ Time Frame: up to 24 months ]
    The mitral valve inflow velocity divided by the average early diastolic tissue velocities of the mitral valve annulus (septal, lateral) measured by tissue Doppler echocardiography.
  • Ventricular-arterial coupling measured by echocardiogram [ Time Frame: up to 24 months ]
    Defined by echocardiography-derived measures of end systolic elastance divided by effective arterial elastance
  • Cardiac Strain measurements by echocardiogram [ Time Frame: up to 24 months ]
    Echocardiography-derived measures of longitudinal, circumferential, and radial strain.
  • Frequency of individuals with clinical heart failure [ Time Frame: up to 24 months ]
    Frequency of clinical heart failure diagnosis
  • High-sensitivity Troponin (hsTnT) level [ Time Frame: up to 24 months ]
    Change in the cardiac biomarker of injury hsTnT over time, defined as a continuous variable
  • N-terminal pro B-type natriuetic peptide (NTproBNP) level [ Time Frame: up to 24 months ]
    Change in the cardiac biomarker of neurohormonal stress NT-proBNP over time, defined as a continuous variable
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab
Official Title  ICMJE A Pilot Study of Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab
Brief Summary Investigators will evaluate the safety, tolerability, and feasibility of a risk-guided cardioprotective treatment strategy with carvedilol, as compared to usual care, in breast cancer patients undergoing treatment with doxorubicin, trastuzumab, or the combination.
Detailed Description This is a single-center, randomized clinical trial that seeks to determine if a risk guided treatment strategy that initiates carvedilol in high risk breast cancer patients prior to doxorubicin and/or trastuzumab is safe, tolerable, and feasible. Subjects who are identified as having elevated CTX Risk by an internally validated clinical risk score (exceeding a pre-specified risk threshold) will be randomized to individually-dosed, open-label carvedilol or usual care. Investigators will use a stratified randomization according to trastuzumab therapy (yes/no) to ensure balance across treatment regimen. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
An internally validated CV risk score will be used to determine an individual patient's risk. Low risk patients will be observed and managed according to usual care. Elevated risk patients will be randomized to open label, individually dosed carvedilol for 1 year or usual care.
Masking: None (Open Label)
Primary Purpose: Supportive Care
Condition  ICMJE
  • Cardiotoxicity
  • Risk Factor, Cardiovascular
  • Toxicity Due to Chemotherapy
  • Breast Cancer
  • Cardiomyopathies
  • Heart Failure
Intervention  ICMJE Drug: Carvedilol
Individually dosed carvedilol
Other Name: Coreg
Study Arms  ICMJE
  • Experimental: Carvedilol

    Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months.

    Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.

    Intervention: Drug: Carvedilol
  • No Intervention: Usual Care
    Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 16, 2019) 		110
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2023
Estimated Primary Completion Date June 30, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Females
  • At least 18 years old
  • Diagnosed with Stage I-III breast cancer with treatment plan to include therapy with anthracyclines and/or trastuzumab in the adjuvant or neo-adjuvant setting
  • Study team is able to obtain all necessary information for calculating Cardiotoxicity Risk Score (including echocardiographic measurement of left ventricular ejection fraction)

Exclusion Criteria:

  • Pregnant or breast feeding. Due to unknown risks and potential harm to the unborn fetus a negative pregnancy test within 10 days prior to enrollment is required in women with child-bearing potential. Due to the potential nursing infant harm, women who are currently breast feeding are not eligible for this study.
  • Contraindication to carvedilol
  • Baseline systolic blood pressure < 90mmHg (if multiple blood pressures are available in the medical record within 1 month prior to screening, the average SBP will be considered)
  • Baseline heart rate < 55 bpm consistent with severe bradycardia (if multiple resting heart rates are available in the medical record within 1 month prior to screening, the average heart rate will be considered)
  • Allergy to carvedilol
  • History of bronchial asthma or related bronchospastic conditions
  • Known history of sick sinus syndrome
  • Severe hepatic impairment, defined as serum bilirubin > 3.0x ULN, AST or ALT > 5.0 ULN within 28 days of enrollment
  • Second- or third-degree AV block, as determined by electrocardiogram
  • Severe bradycardia (unless permanent pacemaker is in place)
  • Patients in cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy
  • Current use of: Bupropion (Wellbutrin), Fluoxetine (Prozac), Paroxetine (Paxil), Quinidine (Quinidex), Duloxetine (Cymbalta), Digoxin
  • Current treatment with beta blocker
  • Unable to provide consent
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bonnie Ky, MD, MSCE 215-573-6606 bonnie.ky@uphs.upenn.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04023110
Other Study ID Numbers  ICMJE UPCC12118
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Investigators do not plan to make the IPD, analytic methods, or study materials available to other researchers for purposes of reproducing our results or replicating the procedure given the pilot Phase 1 nature of this study.
Responsible Party Abramson Cancer Center of the University of Pennsylvania
Study Sponsor  ICMJE Abramson Cancer Center of the University of Pennsylvania
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Bonnie Ky, MD, MSCE Perelman School of Medicine at the University of Pennsylvania
PRS Account Abramson Cancer Center of the University of Pennsylvania
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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