ReProsperHF: Repurposing Probenecid as a Positive Inotrope for the Treatment of Heart Failure

Sponsor

University of Cincinnati (Other)

Overall Status

Completed

CT.gov ID

NCT01814319

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Probenecid is an FDA approved drug for the treatment gout and hyperuricemia. It has been used safely in humans for decades for this and other indications. The investigators have recently discovered that this drug can also stimulate other receptors in the heart and therefore improve its function. The hypothesis of this study is that probenecid can be used to improve the function of the heart and therefore the symptoms in patients with heart failure.

Condition or Disease	Intervention/Treatment	Phase
Systolic Heart Failure	Drug: Probenecid 1 gr oral twice daily Drug: Placebo	Phase 2

Detailed Description

The investigators will test the hypothesis that oral administration of probenecid results in improved symptomatology and heart function in patients with systolic heart failure. There will be three cohorts.

Cohort 1 will enroll up to 50 subjects in a double-blinded, randomized, placebo-control, cross-over study with each patient serving as his or her own control. The subjects will have stable HF, an ejection fraction of less than or equal to 40% and NYHA II to IV symptoms. Each subject will undergo 1 week of investigational product (IP), consisting of oral probenecid therapy 1 gram twice a day or placebo with weekly follow.

The subjects will undergo EKGs, laboratory analysis, physical exams; dyspnea and quality of life questionnaires and a 6 minute walk test (MWT) at baseline. There will be 2 optional sub-studies one for echocardiographic data and the other biomarkers.

Cohort 2 will enroll up to 50 subjects in a double-blinded, randomized, placebo-control study and will include patients admitted to the hospital with acute decompensated HF. Each subject will also receive Investigational product consisting of either 1 gram orally twice daily of probenecid or placebo during their hospitalization. They will have daily follow-up with EKG and appropriate laboratory work. In addition to the EKG, laboratory analysis, physical exams, dyspnea and quality of life questionnaires and 6 MWT data will be collected; additional data such as length of hospital stay, biomarkers, use of inotropic therapy and diuretics, and rate of diuresis will also be collected.

Cohort 3 will enroll up to 50 healthy subjects in a double-blinded, randomized, placebo-control study. Each subject will also receive Investigational product consisting of either 2 grams orally of probenecid or placebo. During a 6 hour course subjects will have laboratory analysis, physical exam, telemetry, EKG and echocardiographic studies performed as measures of both safety and effect of the compound.

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Initial Study on the Use of Probenecid as a Positive Inotrope for the Treatment of Systolic Heart Failure in Stable NYHA Class II to IV Patients

Study Start Date :

Mar 1, 2013

Actual Primary Completion Date :

Jun 1, 2015

Actual Study Completion Date :

Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Probenecid Probenecid 1 gr oral twice daily or placebo will be given to the subject for 1 week (randomly assigned). A subsequent 1 week washout period will occur followed by the alternate therapy.	Drug: Probenecid 1 gr oral twice daily Probenecid 1 gram oral twice daily
Placebo Comparator: placebo Probenecid 1 gr oral twice daily or placebo will be given to the subject for 1 week (randomly assigned). A subsequent 1 week washout period will occur followed by the alternate (placebo) therapy.	Drug: Placebo Matching placebo oral twice daily

Arm

Intervention/Treatment

Experimental: Probenecid

Probenecid 1 gr oral twice daily or placebo will be given to the subject for 1 week (randomly assigned). A subsequent 1 week washout period will occur followed by the alternate therapy.

Drug: Probenecid 1 gr oral twice daily

Probenecid 1 gram oral twice daily

Placebo Comparator: placebo

Probenecid 1 gr oral twice daily or placebo will be given to the subject for 1 week (randomly assigned). A subsequent 1 week washout period will occur followed by the alternate (placebo) therapy.

Drug: Placebo

Matching placebo oral twice daily

Outcome Measures

Primary Outcome Measures

6 minute walk test [1 week]
Measure for changes in the distance that the patient can walk over 6 minutes.
shortness of breath [1 week]
Measure objectively if there are changes in perceived shortness of breath using a standardized scale

Secondary Outcome Measures

Ejection fraction [1 week]
We will measure via echocardiography the systolic function of the heart
beta naturietic peptide [1 week]
We will measure for changes in the beta natuiretic peptide as a marker of cardiac function and dilatation.
serum electrolytes [1 week]
We will measure several important electrolytes such as Na, K and Ca.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

18 years of age or older
EF < 40% via echocardiogram within the past 12 months
Stable dose of heart failure medications for > past 1 month
NYHA class II - IV

Exclusion Criteria

Pregnant or lactating female
Receiving IV inotrope
History of significant non-compliance
Unwilling to adhere to the protocol
Systemic systolic BP less than 90 mmHg at screening visit
History of allergy to probenecid
History of gout
History of renal calculi
Recent unstable coronary artery syndromes (USA, admission to hospital for AMI, revascularization procedure, or acute decompensated HF requiring hospitalization) within the past 3 months.
Implant of CRT device within the past 3 months
TIA, CVA or major surgery within the past 3 months
Valvular heart disease (more than moderate stenosis or insufficiency)
HOCM, myocarditis, constrictive pericarditis, congenital heart disease, 14 Active chemotherapy, significant malignancy or uncontrolled metabolic disease (untreated hyper or hypothyroidism, Cushing's disease etc.)What about uncontrolled DM?? HgA1C > etc
Elevated liver enzymes (> 3 times ULN), 16. Current atrial fibrillation or frequent PVCs (should we define this now) 17. End stage renal disease (dialysis dependent) or worsening renal insufficiency should define now.
History of gastric ulcerations, significant gastroesophageal reflux. 19. Other condition that in the opinion of the investigator, would make the subject a poor candidate for the study.
Co-administration of any medication that in the opinion of the investigator places the subject at increased risks due to potential adverse drug interactions.