TRPV2 Agonists in the Fontan Circulation

Children's Hospital Medical Center, Cincinnati8 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Fontan

Interventions

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Changes in End Diastolic and End Systolic Volume as Measured by Standard and Advanced MRI Parameters

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.

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.

Secondary Outcomes

Changes in Exercise Performance (VO2 Absolute) as Determined by Completing Four Graded Exercise Tests Utilizing a Cycle Ergometer Ramp Protocol; Pre and Post Study Drug and Placebo Administration.

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 Exercise Capacity (Indexed VO2 [ml/kg/Min] of Single Ventricle Patients.

Determine if there is a quantitative difference in indexed VO2 max when patients have been taking the study medication (probenecid) versus a placebo.

Impact of Study Medication on the MRI Ejection Fraction of Single Ventricle Patients.

Determine if there is a quantitative difference in ejection fraction when patients are taking the study medication (probenecid) versus when they are taking a placebo.

Impact of Study Medication on MRI Flow Rates of the Ventricles (Cardiac Output) in Single Ventricle Patients

Determine if there is a quantitative difference in cardiac output of single ventricle patients when taking the study medication (probenecid) versus taking a placebo.

Impact of Study Medication on MRI Strain Values in Single Ventricle Patients

Determine if there is a quantitative difference in longitudinal, circumferential, and radial strain MRI values when subjects take the study medication (probenecid) versus a placebo.