TRPV2 Agonists in the Fontan Circulation

NCT03965351 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: 2017-0541
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

Fontan

Outcome Measures

Primary Outcomes (1)

• 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.

  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 (5)

• 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.

• 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.

• 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.

• 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.

• 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.

Study Arms (2)

Probenecid

EXPERIMENTAL

the study medication (probenecid) as well as a placebo.

Drug: Probenecid; Other: Placebo

Placebo

PLACEBO COMPARATOR

placebo compared to probenecid

Drug: Probenecid; Other: Placebo

Interventions

Probenecid DRUG

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; Probenecid

Placebo OTHER

placebo

Placebo; Probenecid

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Children's Hospital Medical Center, Cincinnati: lead
• American Heart Association: collaborator

Study Sites (1)

Cincinnati Childrens Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

MeSH Terms

Interventions

Probenecid

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds

Results Point of Contact

• Title: Mary Banks
• Organization: Cincinnati Children's Hospital Medical Center

mary.banks@cchmc.org

513-636-2147

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2018
• First Posted: May 29, 2019
• Study Start: March 21, 2017
• Primary Completion: June 30, 2020
• Study Completion: December 31, 2020
• Last Updated: July 9, 2021
• Results First Posted: July 9, 2021

Record last verified: 2021-01

Locations

US (1)