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TRPV2 Agonists in the Fontan Circulation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03965351
Recruitment Status : Active, not recruiting
First Posted : May 29, 2019
Last Update Posted : July 23, 2019
Sponsor:
Collaborator:
American Heart Association
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

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

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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

Resource links provided by the National Library of Medicine

Drug Information available for: Probenecid

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.




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.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03965351


Locations
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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
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Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT03965351    
Other Study ID Numbers: 2017-0541
First Posted: May 29, 2019    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Additional relevant MeSH terms:
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Probenecid
Uricosuric Agents
Gout Suppressants
Antirheumatic Agents
Renal Agents