Trial Outcomes & Findings for TRPV2 Agonists in the Fontan Circulation (NCT NCT03965351)
NCT ID: NCT03965351
Last Updated: 2021-07-09
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE4
Target enrollment
8 participants
Primary outcome timeframe
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.
Results posted on
2021-07-09
Participant Flow
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.
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.
Participant milestones
| Measure |
Probenecid, and Then 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.
|
Placebo, and Then Probenecid
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.
|
|---|---|---|
|
First Intervention (4 Weeks)
STARTED
|
3
|
5
|
|
First Intervention (4 Weeks)
COMPLETED
|
3
|
4
|
|
First Intervention (4 Weeks)
NOT COMPLETED
|
0
|
1
|
|
Wash Out Period (4 Weeks)
STARTED
|
3
|
4
|
|
Wash Out Period (4 Weeks)
COMPLETED
|
3
|
4
|
|
Wash Out Period (4 Weeks)
NOT COMPLETED
|
0
|
0
|
|
Second Intervention (4 Weeks)
STARTED
|
3
|
4
|
|
Second Intervention (4 Weeks)
COMPLETED
|
3
|
3
|
|
Second Intervention (4 Weeks)
NOT COMPLETED
|
0
|
1
|
Reasons for withdrawal
| Measure |
Probenecid, and Then 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.
|
Placebo, and Then Probenecid
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.
|
|---|---|---|
|
First Intervention (4 Weeks)
Lost to Follow-up
|
0
|
1
|
|
Second Intervention (4 Weeks)
Adverse Event
|
0
|
1
|
Baseline Characteristics
TRPV2 Agonists in the Fontan Circulation
Baseline characteristics by cohort
| Measure |
Probenecid, Then Placebo
n=3 Participants
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, Then Probenecid
n=5 Participants
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
n=8 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Categorical
<=18 years
|
1 Participants
n=99 Participants
|
1 Participants
n=107 Participants
|
2 Participants
n=206 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
2 Participants
n=99 Participants
|
4 Participants
n=107 Participants
|
6 Participants
n=206 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Sex: Female, Male
Female
|
1 Participants
n=99 Participants
|
1 Participants
n=107 Participants
|
2 Participants
n=206 Participants
|
|
Sex: Female, Male
Male
|
2 Participants
n=99 Participants
|
4 Participants
n=107 Participants
|
6 Participants
n=206 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
3 Participants
n=99 Participants
|
5 Participants
n=107 Participants
|
8 Participants
n=206 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
Black or African American
|
1 Participants
n=99 Participants
|
1 Participants
n=107 Participants
|
2 Participants
n=206 Participants
|
|
Race (NIH/OMB)
White
|
2 Participants
n=99 Participants
|
4 Participants
n=107 Participants
|
6 Participants
n=206 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Region of Enrollment
United States
|
3 Participants
n=99 Participants
|
5 Participants
n=107 Participants
|
8 Participants
n=206 Participants
|
|
Left ventricle dominant
|
3 participants
n=99 Participants
|
5 participants
n=107 Participants
|
8 participants
n=206 Participants
|
|
Right ventricle dominant
|
0 participants
n=99 Participants
|
0 participants
n=107 Participants
|
0 participants
n=206 Participants
|
PRIMARY outcome
Timeframe: 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.
Outcome measures
| Measure |
Probenecid
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid).
|
Placebo
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication.
|
|---|---|---|
|
Changes in End Diastolic and End Systolic Volume as Measured by Standard and Advanced MRI Parameters
End Systolic Volume
|
3.0 ml
Interval -5.4 to 7.8
|
4.4 ml
Interval 1.8 to 10.9
|
|
Changes in End Diastolic and End Systolic Volume as Measured by Standard and Advanced MRI Parameters
End Diastolic Volume
|
3.3 ml
Interval -2.2 to 8.3
|
3.0 ml
Interval 1.1 to 12.1
|
SECONDARY outcome
Timeframe: 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
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.
Outcome measures
| Measure |
Probenecid
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid).
|
Placebo
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication.
|
|---|---|---|
|
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
Interval 40.0 to 210.0
|
70 ml/min
Interval 10.0 to 90.0
|
SECONDARY outcome
Timeframe: 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.
Outcome measures
| Measure |
Probenecid
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid).
|
Placebo
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication.
|
|---|---|---|
|
Impact of Study Medication on Exercise Capacity (Indexed VO2 [ml/kg/Min] of Single Ventricle Patients.
|
1 ml/kg/min
Interval 1.0 to 4.0
|
1 ml/kg/min
Interval 1.0 to 1.0
|
SECONDARY outcome
Timeframe: 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.
Outcome measures
| Measure |
Probenecid
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid).
|
Placebo
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication.
|
|---|---|---|
|
Impact of Study Medication on the MRI Ejection Fraction of Single Ventricle Patients.
|
-1.2 percent of blood
Interval -3.1 to 2.7
|
-1.1 percent of blood
Interval -4.0 to 2.6
|
SECONDARY outcome
Timeframe: 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.
Outcome measures
| Measure |
Probenecid
n=3 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid).
|
Placebo
n=3 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication.
|
|---|---|---|
|
Impact of Study Medication on MRI Flow Rates of the Ventricles (Cardiac Output) in Single Ventricle Patients
|
0.51 L/min
Interval -0.21 to 0.83
|
-0.21 L/min
Interval -0.53 to 0.68
|
SECONDARY outcome
Timeframe: 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.
Outcome measures
| Measure |
Probenecid
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the study medication (probenecid).
|
Placebo
n=6 Participants
This is a cross-over pilot study. Results are indicative of subject response when receiving the placebo medication.
|
|---|---|---|
|
Impact of Study Medication on MRI Strain Values in Single Ventricle Patients
Longitudinal Strain, systole
|
-2.0 percent
Interval -3.0 to -2.0
|
1.0 percent
Interval -1.0 to 2.0
|
|
Impact of Study Medication on MRI Strain Values in Single Ventricle Patients
Radial strain, diastole
|
-0.31 percent
Interval -1.7 to 1.4
|
0.10 percent
Interval -2.0 to 0.4
|
|
Impact of Study Medication on MRI Strain Values in Single Ventricle Patients
Circumferential Strain, systole
|
2.0 percent
Interval -1.0 to 3.0
|
-1.0 percent
Interval -1.0 to 0.0
|
|
Impact of Study Medication on MRI Strain Values in Single Ventricle Patients
Radial Strain, systole
|
2.5 percent
Interval -2.0 to 11.0
|
0 percent
Interval -12.0 to 8.0
|
|
Impact of Study Medication on MRI Strain Values in Single Ventricle Patients
Longitudinal strain, diastole
|
0.14 percent
Interval 0.08 to 0.19
|
0.20 percent
Interval -1.1 to 0.36
|
|
Impact of Study Medication on MRI Strain Values in Single Ventricle Patients
Circumferential strain, diastole
|
-0.23 percent
Interval -0.31 to 0.02
|
0.10 percent
Interval -0.44 to 0.68
|
Adverse Events
Probenecid
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Placebo
Serious events: 1 serious events
Other events: 4 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Probenecid
n=8 participants at risk
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.
|
Placebo
n=8 participants at risk
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.
|
|---|---|---|
|
Gastrointestinal disorders
Contraindicated Medication Taken
|
0.00%
0/8 • 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
|
12.5%
1/8 • Number of events 1 • 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
|
|
Gastrointestinal disorders
Overdose of study medication
|
0.00%
0/8 • 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
|
12.5%
1/8 • Number of events 1 • 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
|
|
Cardiac disorders
Hospital Admission
|
0.00%
0/8 • 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
|
12.5%
1/8 • Number of events 1 • 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
|
Other adverse events
| Measure |
Probenecid
n=8 participants at risk
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.
|
Placebo
n=8 participants at risk
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.
|
|---|---|---|
|
General disorders
Sore Throat
|
12.5%
1/8 • Number of events 1 • 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
|
12.5%
1/8 • Number of events 2 • 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
|
|
General disorders
Loss of appetite
|
0.00%
0/8 • 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
|
12.5%
1/8 • Number of events 1 • 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
|
|
Gastrointestinal disorders
Abdominal Pain
|
0.00%
0/8 • 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
|
25.0%
2/8 • Number of events 2 • 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
|
|
General disorders
Fatigue
|
0.00%
0/8 • 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
|
12.5%
1/8 • Number of events 1 • 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
|
|
Gastrointestinal disorders
Nausea
|
12.5%
1/8 • Number of events 1 • 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
|
12.5%
1/8 • Number of events 1 • 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
|
|
Immune system disorders
Rhinovirus
|
12.5%
1/8 • Number of events 2 • 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
|
0.00%
0/8 • 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
|
|
General disorders
Migraine
|
12.5%
1/8 • Number of events 1 • 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
|
0.00%
0/8 • 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
|
|
Metabolism and nutrition disorders
Weight Gain
|
0.00%
0/8 • 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
|
12.5%
1/8 • Number of events 1 • 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
|
|
Blood and lymphatic system disorders
Elevated NT-proBNP
|
0.00%
0/8 • 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
|
12.5%
1/8 • Number of events 1 • 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
|
Additional Information
Mary Banks
Cincinnati Children's Hospital Medical Center
Phone: 513-636-2147
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place