Fontan
Conditions
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.
Interventions
DRUGProbenecid
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.
OTHERPlacebo
placebo
Sponsors
American Heart Association
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in End Diastolic and End Systolic Volume as Measured by Standard and Advanced MRI Parameters | 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
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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 Exercise Capacity (Indexed VO2 [ml/kg/Min] of Single Ventricle Patients. | 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 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. | 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 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 | 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 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 | 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 longitudinal, circumferential, and radial strain MRI values when subjects take the study medication (probenecid) versus a placebo. |
Countries
United States
Participant flow
Recruitment details
This was a prospective randomized, placebo-controlled cross-over pilot study of up to 22 patients who have had a prior Fontan operation for single ventricle physiology who are ≥ 10 years old. Each patient completed a total of four study visits over the course of a 4 month period.
Pre-assignment details
Each patient came in for a baseline assessment visit. At the end of the baseline visit they received either probenecid or placebo. They took the medication for a month and then returned for the second visit. A washout period occurred for a month and then study patients returned for visit three where they received either probenecid or placebo; whichever was not received during visit one. This medication was taken for a month and then patients returned for the final visit.
Participants by arm
| Arm | Count |
|---|---|
| Probenecid, Then Placebo the study medication (probenecid) as well as a placebo.
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.
Placebo: placebo | 3 |
| Placebo, Then Probenecid placebo compared to probenecid
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.
Placebo: placebo | 5 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (4 Weeks) | Lost to Follow-up | 0 | 1 |
| Second Intervention (4 Weeks) | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Probenecid, Then Placebo | Placebo, Then Probenecid | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Left ventricle dominant | 3 participants | 5 participants | 8 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 4 Participants | 6 Participants |
| Region of Enrollment United States | 3 Participants | 5 Participants | 8 Participants |
| Right ventricle dominant | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 1 / 8 | 4 / 8 |
| serious Total, serious adverse events | 0 / 8 | 1 / 8 |
Outcome results
Primary
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Probenecid | Changes in End Diastolic and End Systolic Volume as Measured by Standard and Advanced MRI Parameters | End Diastolic Volume | 3.3 ml |
| Probenecid | Changes in End Diastolic and End Systolic Volume as Measured by Standard and Advanced MRI Parameters | End Systolic Volume | 3.0 ml |
| Placebo | Changes in End Diastolic and End Systolic Volume as Measured by Standard and Advanced MRI Parameters | End Diastolic Volume | 3.0 ml |
| Placebo | Changes in End Diastolic and End Systolic Volume as Measured by Standard and Advanced MRI Parameters | End Systolic Volume | 4.4 ml |
Secondary
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.
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.
Population: Max VO2 Absolute
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Probenecid | 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. | 40 ml/min |
| Placebo | 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. | 70 ml/min |
Secondary
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Probenecid | Impact of Study Medication on Exercise Capacity (Indexed VO2 [ml/kg/Min] of Single Ventricle Patients. | 1 ml/kg/min |
| Placebo | Impact of Study Medication on Exercise Capacity (Indexed VO2 [ml/kg/Min] of Single Ventricle Patients. | 1 ml/kg/min |
Secondary
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Probenecid | Impact of Study Medication on MRI Flow Rates of the Ventricles (Cardiac Output) in Single Ventricle Patients | 0.51 L/min |
| Placebo | Impact of Study Medication on MRI Flow Rates of the Ventricles (Cardiac Output) in Single Ventricle Patients | -0.21 L/min |
Secondary
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.
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Probenecid | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Longitudinal Strain, systole | -2.0 percent |
| Probenecid | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Circumferential Strain, systole | 2.0 percent |
| Probenecid | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Radial Strain, systole | 2.5 percent |
| Probenecid | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Longitudinal strain, diastole | 0.14 percent |
| Probenecid | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Circumferential strain, diastole | -0.23 percent |
| Probenecid | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Radial strain, diastole | -0.31 percent |
| Placebo | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Circumferential strain, diastole | 0.10 percent |
| Placebo | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Longitudinal Strain, systole | 1.0 percent |
| Placebo | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Longitudinal strain, diastole | 0.20 percent |
| Placebo | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Circumferential Strain, systole | -1.0 percent |
| Placebo | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Radial strain, diastole | 0.10 percent |
| Placebo | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients | Radial Strain, systole | 0 percent |
Secondary
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Probenecid | Impact of Study Medication on the MRI Ejection Fraction of Single Ventricle Patients. | -1.2 percent of blood |
| Placebo | Impact of Study Medication on the MRI Ejection Fraction of Single Ventricle Patients. | -1.1 percent of blood |