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出境医 / 临床实验 / TRPV2 Agonists in the Fontan Circulation

TRPV2 Agonists in the Fontan Circulation

Study Description
Brief Summary:
There are currently very few proven pharmacologic options available for these patients. The recent discovery of transient receptor potential vanilloid (TRPV) channels, particularly TRPV2 channels, in the cardiovascular system is promising as a potential pathway for pharmacologic intervention for Fontan patients. Probenecid, a drug best known as a treatment for gout or as a penicillin adjunct, acts as a TRPV2 agonist and has recently become the subject of study as a model therapy for the treatment of cardiomyopathy due to its positive inotropic and lusitropic effects. The purpose of this pilot study is to determine if probenecid will improve magnetic resonance (MRI) parameters of systolic and/or diastolic dysfunction as well as associated symptoms in patients with a Fontan circulation. The investigators will quantitatively assess functional improvement with pre- and post-treatment cardiopulmonary exercise testing.

Condition or disease Intervention/treatment Phase
Fontan Drug: Probenecid Phase 4

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: TRPV2 Agonists in Fontan Circulation Patients
Actual Study Start Date : March 21, 2017
Actual Primary Completion Date : June 30, 2019
Estimated Study Completion Date : December 31, 2019
Arms and Interventions
Arm Intervention/treatment
Experimental: Single Left Ventricle
We will be recruiting 11 individuals who have a dominant left ventricle. Subjects will receive both the study medication (probenecid) as well as a placebo.
 Drug: Probenecid
This is a cross-over pilot study where participants will receive both the study medication (probenecid), as well as a placebo to see if the study medication improves magnetic resonance parameters of systolic and diastolic dysfunction that occurs in the Fontan population.
Experimental: Single Right Ventricle
We will be recruiting 11 individuals who have a dominant right ventricle. Subjects will receive both the study medication (probenecid) as well as a placebo.
 Drug: Probenecid
This is a cross-over pilot study where participants will receive both the study medication (probenecid), as well as a placebo to see if the study medication improves magnetic resonance parameters of systolic and diastolic dysfunction that occurs in the Fontan population.
Outcome Measures
Primary Outcome Measures :
  1. Changes in ejection fraction as measured by standard and advanced MRI parameters [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if Fontan patients treated with probenecid for four weeks will experience increased systolic and diastolic function (as measured via standard and advanced MRI parameters) compared with four weeks of placebo. Participants will be assigned to either the placebo arm or study medication arm for the first four weeks. They will then undergo a four week wash out period. Finally, participants will be placed into the study arm that they were not assigned to in the first four weeks when they return for the last four weeks of study participation. There will be four MRI scans over the course of the 12 week study period.


Secondary Outcome Measures :
  1. Changes in exercise performance as determined by completing four graded exercise tests utilizing a cycle ergometer ramp protocol; pre and post study drug and placebo administration. [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if Fontan patients treated with probenecid for four weeks will experience improved exercise performance compared with four weeks of placebo as measured by a maximal graded exercise test. Participants will complete a graded maximal cycle ergometer test at each of their four study visits.

  2. Impact of study medication on left ventricular dominant versus right ventricular dominant patients in terms of exercise capacity [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if there is a quantitative difference in patients who have a left dominant ventricle versus a right dominant ventricle after treatment with study medication. This measurement will be determined through data analysis upon study completion to determine if there is more benefit to left ventricular dominant or right ventricular dominant patients when taking this medication.

  3. Impact of study medication on left ventricular dominant versus right ventricular dominant patients in terms of MRI ejection fraction of the ventricles [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if there is a quantitative difference in patients who have a left dominant ventricle versus a right dominant ventricle after treatment with study medication. This measurement will be determined through data analysis upon study completion to determine if there is more benefit to left ventricular dominant or right ventricular dominant patients when taking this medication.

  4. Impact of study medication on left ventricular dominant versus right ventricular dominant patients in terms of MRI flow rates of the ventricles [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if there is a quantitative difference in patients who have a left dominant ventricle versus a right dominant ventricle after treatment with study medication. This measurement will be determined through data analysis upon study completion to determine if there is more benefit to left ventricular dominant or right ventricular dominant patients when taking this medication.

  5. Impact of study medication on left ventricular dominant versus right ventricular dominant patients in terms of MRI strain values of the ventricles [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if there is a quantitative difference in patients who have a left dominant ventricle versus a right dominant ventricle after treatment with study medication. This measurement will be determined through data analysis upon study completion to determine if there is more benefit to left ventricular dominant or right ventricular dominant patients when taking this medication.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. ≥ 12 years old
  2. Single ventricle congenital heart disease status post Fontan procedure.

  3. Impaired ventricular function as assessed by preexisting echocardiographic studies and any available MRI studies.

    1. LV inclusion criteria: Ejection fraction by cMRI or echo assessment of <50% or moderate to severe dysfunction.
    2. RV inclusion criteria: Ejection fraction by cMRI of <45% or moderate to severe dysfunction. Or, given the ASE recommendation to avoid use of 2-D imaging quantification for assessment of right ventricular systolic function, a peak global longitudinal strain value as assessed by a single reviewer with a value greater than -17% will also be included. Peak global longitudinal strain analysis will be performed for all eligible single right ventricles noted by subjective echo reports to have abnormal systolic function if no qualifying cardiac MRI assessment of ejection fraction is available.

Exclusion Criteria:

  1. Clinically unstable or ongoing illness.
  2. Evidence of untreated Fontan pathway obstruction.
  3. Presence of uncontrolled arrhythmias.
  4. Evidence of moderate or greater atrioventricular valve regurgitation.
  5. Pregnancy.
  6. History of sulfonamide allergy
  7. Known G6PD deficiency
  8. Patients on certain drugs that have potentially dangerous interactions with probenecid: doripenem, zalcitabine, deferiperone, citalopram, methotrexate, ciprofloxacin, amoxicillin, cefprozil, cefpodoxime, cefotaxime, meropenem, ertapenem, valganciclovir, ganciclovir, ziovudine ketorolac, cefdinir, cephalexin, dapsone, indomethacin, and piperacillin.Each subject's medication list will be reviewed prior to study participation.
  9. Impaired renal function as defined by a GFR < 60mL/min/1.73 m2 within the last year.
  10. Patients at a higher risk for arrhythmia including those with a prior history of arrhythmia including atrial and ventricular dysrhythmia or those on established anti-arrhythmic therapy.
  11. Admission to the hospital due to a clinically significant arrhythmia within the previous month.
  12. Greater than moderate atrioventricular regurgitation as denoted on most recent echo report.
  13. Patients with atrio-pulmonary Fontan
  14. Currently enrolled in an interventional drug trial or completed an interventional drug trial within the past 30 days.
  15. Not appropriate for MRI screening due to having an implanted device.
Contacts and Locations

Locations
Layout table for location information
United States, Ohio
Cincinnati Childrens Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
American Heart Association
Tracking Information
First Submitted Date  ICMJE May 16, 2018
First Posted Date  ICMJE May 29, 2019
Last Update Posted Date July 23, 2019
Actual Study Start Date  ICMJE March 21, 2017
Actual Primary Completion Date June 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 24, 2019) 		Changes in ejection fraction as measured by standard and advanced MRI parameters [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
Determine if Fontan patients treated with probenecid for four weeks will experience increased systolic and diastolic function (as measured via standard and advanced MRI parameters) compared with four weeks of placebo. Participants will be assigned to either the placebo arm or study medication arm for the first four weeks. They will then undergo a four week wash out period. Finally, participants will be placed into the study arm that they were not assigned to in the first four weeks when they return for the last four weeks of study participation. There will be four MRI scans over the course of the 12 week study period.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • Changes in exercise performance as determined by completing four graded exercise tests utilizing a cycle ergometer ramp protocol; pre and post study drug and placebo administration. [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if Fontan patients treated with probenecid for four weeks will experience improved exercise performance compared with four weeks of placebo as measured by a maximal graded exercise test. Participants will complete a graded maximal cycle ergometer test at each of their four study visits.
  • Impact of study medication on left ventricular dominant versus right ventricular dominant patients in terms of exercise capacity [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if there is a quantitative difference in patients who have a left dominant ventricle versus a right dominant ventricle after treatment with study medication. This measurement will be determined through data analysis upon study completion to determine if there is more benefit to left ventricular dominant or right ventricular dominant patients when taking this medication.
  • Impact of Study Medication on Left Ventricular Dominant Versus Right Ventricular Dominant Patients in Terms of MRI Ejection Fraction of the Ventricles [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if there is a quantitative difference in patients who have a left dominant ventricle versus a right dominant ventricle after treatment with study medication. This measurement will be determined through data analysis upon study completion to determine if there is more benefit to left ventricular dominant or right ventricular dominant patients when taking this medication.
  • Impact of study medication on left ventricular dominant versus right ventricular dominant patients in terms of MRI flow rates of the ventricles [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if there is a quantitative difference in patients who have a left dominant ventricle versus a right dominant ventricle after treatment with study medication. This measurement will be determined through data analysis upon study completion to determine if there is more benefit to left ventricular dominant or right ventricular dominant patients when taking this medication.
  • Impact of Study Medication on Left Ventricular Dominant Versus Right Ventricular Dominant Patients in Terms of MRI Strain Values of the Ventricles [ Time Frame: Total time participation in the study will be twelve weeks. Four weeks on the placebo or study medication, four weeks of a washout period and another four weeks with the study medication or placebo. ]
    Determine if there is a quantitative difference in patients who have a left dominant ventricle versus a right dominant ventricle after treatment with study medication. This measurement will be determined through data analysis upon study completion to determine if there is more benefit to left ventricular dominant or right ventricular dominant patients when taking this medication.
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 TRPV2 Agonists in the Fontan Circulation
Official Title  ICMJE TRPV2 Agonists in Fontan Circulation Patients
Brief Summary There are currently very few proven pharmacologic options available for these patients. The recent discovery of transient receptor potential vanilloid (TRPV) channels, particularly TRPV2 channels, in the cardiovascular system is promising as a potential pathway for pharmacologic intervention for Fontan patients. Probenecid, a drug best known as a treatment for gout or as a penicillin adjunct, acts as a TRPV2 agonist and has recently become the subject of study as a model therapy for the treatment of cardiomyopathy due to its positive inotropic and lusitropic effects. The purpose of this pilot study is to determine if probenecid will improve magnetic resonance (MRI) parameters of systolic and/or diastolic dysfunction as well as associated symptoms in patients with a Fontan circulation. The investigators will quantitatively assess functional improvement with pre- and post-treatment cardiopulmonary exercise testing.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Fontan
Intervention  ICMJE Drug: Probenecid
This is a cross-over pilot study where participants will receive both the study medication (probenecid), as well as a placebo to see if the study medication improves magnetic resonance parameters of systolic and diastolic dysfunction that occurs in the Fontan population.
Study Arms  ICMJE
  • Experimental: Single Left Ventricle
    We will be recruiting 11 individuals who have a dominant left ventricle. Subjects will receive both the study medication (probenecid) as well as a placebo.
    Intervention: Drug: Probenecid
  • Experimental: Single Right Ventricle
    We will be recruiting 11 individuals who have a dominant right ventricle. Subjects will receive both the study medication (probenecid) as well as a placebo.
    Intervention: Drug: Probenecid
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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 22, 2019) 		8
Original Estimated Enrollment  ICMJE
 (submitted: May 24, 2019) 		22
Estimated Study Completion Date  ICMJE December 31, 2019
Actual Primary Completion Date June 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. ≥ 12 years old
  2. Single ventricle congenital heart disease status post Fontan procedure.

  3. Impaired ventricular function as assessed by preexisting echocardiographic studies and any available MRI studies.

    1. LV inclusion criteria: Ejection fraction by cMRI or echo assessment of <50% or moderate to severe dysfunction.
    2. RV inclusion criteria: Ejection fraction by cMRI of <45% or moderate to severe dysfunction. Or, given the ASE recommendation to avoid use of 2-D imaging quantification for assessment of right ventricular systolic function, a peak global longitudinal strain value as assessed by a single reviewer with a value greater than -17% will also be included. Peak global longitudinal strain analysis will be performed for all eligible single right ventricles noted by subjective echo reports to have abnormal systolic function if no qualifying cardiac MRI assessment of ejection fraction is available.

Exclusion Criteria:

  1. Clinically unstable or ongoing illness.
  2. Evidence of untreated Fontan pathway obstruction.
  3. Presence of uncontrolled arrhythmias.
  4. Evidence of moderate or greater atrioventricular valve regurgitation.
  5. Pregnancy.
  6. History of sulfonamide allergy
  7. Known G6PD deficiency
  8. Patients on certain drugs that have potentially dangerous interactions with probenecid: doripenem, zalcitabine, deferiperone, citalopram, methotrexate, ciprofloxacin, amoxicillin, cefprozil, cefpodoxime, cefotaxime, meropenem, ertapenem, valganciclovir, ganciclovir, ziovudine ketorolac, cefdinir, cephalexin, dapsone, indomethacin, and piperacillin.Each subject's medication list will be reviewed prior to study participation.
  9. Impaired renal function as defined by a GFR < 60mL/min/1.73 m2 within the last year.
  10. Patients at a higher risk for arrhythmia including those with a prior history of arrhythmia including atrial and ventricular dysrhythmia or those on established anti-arrhythmic therapy.
  11. Admission to the hospital due to a clinically significant arrhythmia within the previous month.
  12. Greater than moderate atrioventricular regurgitation as denoted on most recent echo report.
  13. Patients with atrio-pulmonary Fontan
  14. Currently enrolled in an interventional drug trial or completed an interventional drug trial within the past 30 days.
  15. Not appropriate for MRI screening due to having an implanted device.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03965351
Other Study ID Numbers  ICMJE 2017-0541
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Children's Hospital Medical Center, Cincinnati
Study Sponsor  ICMJE Children's Hospital Medical Center, Cincinnati
Collaborators  ICMJE American Heart Association
Investigators  ICMJE Not Provided
PRS Account Children's Hospital Medical Center, Cincinnati
Verification Date July 2019

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

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