TRPV2 Agonists in the Fontan Circulation
Study Details
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 |
|---|---|---|
|
Phase 4 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Probenecid 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.
Other: Placebo
placebo
|
| Placebo Comparator: Placebo placebo compared to probenecid |
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.
Other: Placebo
placebo
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
≥ 12 years old
-
Single ventricle congenital heart disease status post Fontan procedure.
-
Impaired ventricular function as assessed by preexisting echocardiographic studies and any available MRI studies.
-
LV inclusion criteria: Ejection fraction by cMRI or echo assessment of <50% or moderate to severe dysfunction.
-
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:
-
Clinically unstable or ongoing illness.
-
Evidence of untreated Fontan pathway obstruction.
-
Presence of uncontrolled arrhythmias.
-
Evidence of moderate or greater atrioventricular valve regurgitation.
-
Pregnancy.
-
History of sulfonamide allergy
-
Known G6PD deficiency
-
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.
-
Impaired renal function as defined by a GFR < 60mL/min/1.73 m2 within the last year.
-
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.
-
Admission to the hospital due to a clinically significant arrhythmia within the previous month.
-
Greater than moderate atrioventricular regurgitation as denoted on most recent echo report.
-
Patients with atrio-pulmonary Fontan
-
Currently enrolled in an interventional drug trial or completed an interventional drug trial within the past 30 days.
-
Not appropriate for MRI screening due to having an implanted device.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Cincinnati Childrens Hospital Medical Center | Cincinnati | Ohio | United States | 45229 |
Sponsors and Collaborators
- Children's Hospital Medical Center, Cincinnati
- American Heart Association
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.- 2017-0541
Study Results
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 Detail | 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. |
| Arm/Group Title | Probenecid, and Then Placebo | Placebo, and Then Probenecid |
|---|---|---|
| Arm/Group Description | All patients will have a baseline assessment immediately preceding initiation of probenecid or placebo. This will include a physical exam to assess any clinical symptoms, review of cardiac symptoms, blood work, pregnancy test for those girls/women of child bearing potential, PEDS QL questionnaire completion, exercise testing and MRI, as described in detail below. Patients will then receive either probenecid or placebo for 28(±7 days) of treatment according to their randomization group, after which the same testing will be repeated. Following 28(±7 days) of washout, patients will undergo the same testing procedures as during the first period of study but with the alternate treatment. To assist in achieving congruence between clinical testing performed and desired pre-intervention testing, we will coordinate with each patient and his/her cardiologist prior to the clinical visit. Patients will receive a one month supply of oral probenecid therapy with the following dosing regimen: For patients (adults and pediatric) ≥ 40 kg: 500 mg by mouth twice daily. For children 10-17 years old and < 40 kg: 250 mg by mouth twice daily During the placebo treatment arm, patients will receive 28(±7 days) of placebo therapy. Oral placebo therapy will be twice daily, with an identical dosing regimen as the placebo. | All patients will have a baseline assessment immediately preceding initiation of probenecid or placebo. This will include a physical exam to assess any clinical symptoms, review of cardiac symptoms, blood work, pregnancy test for those girls/women of child bearing potential, PEDS QL questionnaire completion, exercise testing and MRI, as described in detail below. Patients will then receive either probenecid or placebo for 28(±7 days) of treatment according to their randomization group, after which the same testing will be repeated. Following 28(±7 days) of washout, patients will undergo the same testing procedures as during the first period of study but with the alternate treatment. To assist in achieving congruence between clinical testing performed and desired pre-intervention testing, we will coordinate with each patient and his/her cardiologist prior to the clinical visit. Patients will receive a one month supply of oral probenecid therapy with the following dosing regimen: For patients (adults and pediatric) ≥ 40 kg: 500 mg by mouth twice daily. For children 10-17 years old and < 40 kg: 250 mg by mouth twice daily During the placebo treatment arm, patients will receive 28(±7 days) of placebo therapy. Oral placebo therapy will be twice daily, with an identical dosing regimen as the placebo. |
| Period Title: First Intervention (4 Weeks) | ||
| STARTED | 3 | 5 |
| COMPLETED | 3 | 4 |
| NOT COMPLETED | 0 | 1 |
| Period Title: First Intervention (4 Weeks) | ||
| STARTED | 3 | 4 |
| COMPLETED | 3 | 4 |
| NOT COMPLETED | 0 | 0 |
| Period Title: First Intervention (4 Weeks) | ||
| STARTED | 3 | 4 |
| COMPLETED | 3 | 3 |
| NOT COMPLETED | 0 | 1 |
Baseline Characteristics
| Arm/Group Title | Probenecid, Then Placebo | Placebo, Then Probenecid | Total |
|---|---|---|---|
| Arm/Group Description | 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 | 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 | Total of all reporting groups |
| Overall Participants | 3 | 5 | 8 |
| Age (Count of Participants) | |||
| <=18 years |
1
33.3%
|
1
20%
|
2
25%
|
| Between 18 and 65 years |
2
66.7%
|
4
80%
|
6
75%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
1
33.3%
|
1
20%
|
2
25%
|
| Male |
2
66.7%
|
4
80%
|
6
75%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
3
100%
|
5
100%
|
8
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
1
33.3%
|
1
20%
|
2
25%
|
| White |
2
66.7%
|
4
80%
|
6
75%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (Count of Participants) | |||
| United States |
3
100%
|
5
100%
|
8
100%
|
| Left ventricle dominant (participants) [Number] | |||
| Number [participants] |
3
100%
|
5
100%
|
8
100%
|
| Right ventricle dominant (participants) [Number] | |||
| Number [participants] |
0
0%
|
0
0%
|
0
0%
|
Outcome Measures
| Title | Changes in End Diastolic and End Systolic Volume as Measured by Standard and Advanced MRI Parameters |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Probenecid | Placebo |
|---|---|---|
| Arm/Group Description | This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid). | This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication. |
| Measure Participants | 6 | 6 |
| End Diastolic Volume |
3.3
|
3.0
|
| End Systolic Volume |
3.0
|
4.4
|
| Title | 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. |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Max VO2 Absolute |
| Arm/Group Title | Probenecid | Placebo |
|---|---|---|
| Arm/Group Description | This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid). | This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication. |
| Measure Participants | 6 | 6 |
| Mean (Inter-Quartile Range) [ml/min] |
40
|
70
|
| Title | Impact of Study Medication on Exercise Capacity (Indexed VO2 [ml/kg/Min] of Single Ventricle Patients. |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Probenecid | Placebo |
|---|---|---|
| Arm/Group Description | This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid). | This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication. |
| Measure Participants | 6 | 6 |
| Median (Inter-Quartile Range) [ml/kg/min] |
1
|
1
|
| Title | Impact of Study Medication on the MRI Ejection Fraction of Single Ventricle Patients. |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Probenecid | Placebo |
|---|---|---|
| Arm/Group Description | This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid). | This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication. |
| Measure Participants | 6 | 6 |
| Median (Inter-Quartile Range) [percent of blood] |
-1.2
|
-1.1
|
| Title | Impact of Study Medication on MRI Flow Rates of the Ventricles (Cardiac Output) in Single Ventricle Patients |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Probenecid | Placebo |
|---|---|---|
| Arm/Group Description | This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid). | This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication. |
| Measure Participants | 3 | 3 |
| Median (Inter-Quartile Range) [L/min] |
0.51
|
-0.21
|
| Title | Impact of Study Medication on MRI Strain Values in Single Ventricle Patients |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Probenecid | Placebo |
|---|---|---|
| Arm/Group Description | This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid). | This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication. |
| Measure Participants | 6 | 6 |
| Longitudinal Strain, systole |
-2.0
|
1.0
|
| Circumferential Strain, systole |
2.0
|
-1.0
|
| Radial Strain, systole |
2.5
|
0
|
| Longitudinal strain, diastole |
0.14
|
0.20
|
| Circumferential strain, diastole |
-0.23
|
0.10
|
| Radial strain, diastole |
-0.31
|
0.10
|
Adverse Events
| Time Frame | Adverse event data was collected on a per patient basis from the beginning of enrollment at consent to subject completion or withdrawal (whichever came first) up to a maximum of 16 weeks | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Probenecid | Placebo | ||
| Arm/Group Description | Participants in this arm were randomly assigned to receive probenecid (study medication) during the first phase, then went through a washout phase, and finally received a placebo during the last phase. | Participants in this arm were randomly assigned to receive placebo during the first phase, then went through a washout phase, and finally received the study medication, probenecid, during the last phase. | ||
All Cause Mortality |
||||
| Probenecid | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/8 (0%) | 0/8 (0%) | ||
Serious Adverse Events |
||||
| Probenecid | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/8 (0%) | 1/8 (12.5%) | ||
| Cardiac disorders | ||||
| Hospital Admission | 0/8 (0%) | 0 | 1/8 (12.5%) | 1 |
| Gastrointestinal disorders | ||||
| Contraindicated Medication Taken | 0/8 (0%) | 0 | 1/8 (12.5%) | 1 |
| Overdose of study medication | 0/8 (0%) | 0 | 1/8 (12.5%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Probenecid | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/8 (12.5%) | 4/8 (50%) | ||
| Blood and lymphatic system disorders | ||||
| Elevated NT-proBNP | 0/8 (0%) | 0 | 1/8 (12.5%) | 1 |
| Gastrointestinal disorders | ||||
| Abdominal Pain | 0/8 (0%) | 0 | 2/8 (25%) | 2 |
| Nausea | 1/8 (12.5%) | 1 | 1/8 (12.5%) | 1 |
| General disorders | ||||
| Sore Throat | 1/8 (12.5%) | 1 | 1/8 (12.5%) | 2 |
| Loss of appetite | 0/8 (0%) | 0 | 1/8 (12.5%) | 1 |
| Fatigue | 0/8 (0%) | 0 | 1/8 (12.5%) | 1 |
| Migraine | 1/8 (12.5%) | 1 | 0/8 (0%) | 0 |
| Immune system disorders | ||||
| Rhinovirus | 1/8 (12.5%) | 2 | 0/8 (0%) | 0 |
| Metabolism and nutrition disorders | ||||
| Weight Gain | 0/8 (0%) | 0 | 1/8 (12.5%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Mary Banks |
|---|---|
| Organization | Cincinnati Children's Hospital Medical Center |
| Phone | 513-636-2147 |
| mary.banks@cchmc.org |
- 2017-0541