Safety and Cardiovascular Efficacy of Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD

Study Overview
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Brief Summary
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This study is a pilot study designed to compare the safety and cardiovascular effects of 26 weeks of combination hydralazine/isorsorbide dinitrate therapy with placebo therapy in patients receiving chronic hemodialysis. The investigators hypothesize that treatment of chronic hemodialysis (ESRD) patients with a combination of hydralazine/isosorbide dinitrate compared with placebo is safe and that it will improve heart function as well blood flow/blood vessel supply.

Detailed Description
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Sixteen patients receiving maintenance hemodialysis will be randomized to 26 weeks of therapy with combination hydralazine/isosorbide dinitrate or placebo. Study medications will be titrated to goal dose during the first 4 weeks and maintained at goal dose (as tolerated) between weeks 4-26. A final study visit to assess symptoms after drug discontinuation will occur 4 weeks after drug discontinuation. Study duration-Maximum of 32 weeks with 26 weeks of active therapy. Efficacy Measures -Tissue Doppler echocardiography and myocardial perfusion scanning using radioactive NH3 PET will be assessed at weeks 0 and 26. Safety Measures-Adverse events rates including inter- and intra-dialytic hypotension, ,cardiovascular death and gastrointestinal symptoms will be assessed throughout the duration of the study.

Official Title
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A Phase IV Randomized, Double-blind, Active-controlled, Single-center Study of the Safety and Effects on Cardiac Structure and Function of Hydralazine and Isosorbide Dinitrate in Patients With Hemodialysis Dependent ESRD

Conditions
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Chronic Hemodialysis (ESRD)

Intervention / Treatment
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* Drug: Hydralazine/Isorsorbide Dinitrate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Maintenance hemodialysis therapy for end-stage renal disease Age 18-85 years ≥ 90 days since dialysis initiation Ability to provide informed consent Pre-dialysis seated systolic blood pressure measurements must be ≥ 120 mm Hg in the 2 weeks before enrollment and on the day of randomization. Exclusion Criteria Serum potassium ≥6.5 mEq/L within 2 months prior to screening Unscheduled dialysis for hyperkalemia within the 3 months prior to screening Hypotension defined as pre-dialysis SBP <100 mm Hg (seated measurement) within 4 weeks prior to enrollment Recurrent intra-dialytic hypotension, defined as systolic blood pressure <80 mm Hg during ≥3 dialysis sessions per 30-day rolling period or treatment for either hypotension or symptoms of hypotension if systolic blood pressure is < 100 mm Hg during ≥3 dialysis sessions per 30-day rolling period. Mitral valve repair or replacement Severe mitral valve disease by echocardiography, coronary angiography or cardiac magnetic resonance imaging Prior coronary artery bypass graft Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another dialysis unit within 6 months Expected survival < 6 months Allergy to study medications (ISD, HY, adenosine/diprimidole) Active use of sildenafil, vardenafil or tadalafil History of severe aortic stenosis or other cause of LV outflow obstruction Pregnancy, anticipated pregnancy, or breastfeeding, confirmed by serum pregnancy test on the day of PET scan Incarceration Participation in another intervention study Use of monoamine oxidase inhibitors Contraindication to adenosine including 2nd or 3rd degree heart block, sick sinus syndrome or symptomatic bradycardia (without a functioning pacemaker) moderate or severe asthma chronic obstructive pulmonary disease Active use of any of the study medications unless participant and physician willing to discontinue prior to enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydralazine/Isorsorbide Dinitrate<br>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events. Allowable Dosage Forms: ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day | Drug: Hydralazine/Isorsorbide Dinitrate<br>* Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events. Target Dose: Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day Allowable Dosage Forms: ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day Dose Titration: ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.<br>* Other names: Isordil;|
| Active Comparator: Placebo<br>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events. | Drug: Placebo<br>* Placebo titration will mimic titration of active study arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | Rate of primary Safety Outcomes(hypotension, serious adverse events, GI events and CV death) | 6 months | 
| Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months | Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography | 0 to 6 months | 
| Change in E' on TDI Echo From 0-6 Months | Co-primary efficacy measure measured on Tissue Doppler Echocardiography | 0 to 6 months | 
| Reduction in Drug Dose or Discontinuation of Study Drug | Primary Tolerability measure | 0 to 6 months | 
| Number of Patients Completing Study From 0 to 6 Months | Primary Feasibility Measure | 0 to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Circulating Fibrosis Markers and Angiogenesis Markers | Circulating concentrations of markers such as the carboxy terminal of pro-collagen type 1 or ADMA will be measured | 0 to 6 months | 
| Change in LVMI | Change in left ventricular mass index between baseline and 6 months. | 0 to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemodialysis, ESRD, Cardiovascular Disease, Isosorbide Dinitrate, Hydralazine