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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Hemodialysis (ESRD)
• Intervention / Treatment: Drug: Hydralazine/Isorsorbide Dinitrate; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Maintenance hemodialysis therapy for end-stage renal disease
2. Age 18-85 years
3. ≥ 90 days since dialysis initiation
4. Ability to provide informed consent
5. 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

1. Serum potassium ≥6.5 mEq/L within 2 months prior to screening
2. Unscheduled dialysis for hyperkalemia within the 3 months prior to screening
3. Hypotension defined as pre-dialysis SBP <100 mm Hg (seated measurement) within 4 weeks prior to enrollment
4. 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.
5. Mitral valve repair or replacement
6. Severe mitral valve disease by echocardiography, coronary angiography or cardiac magnetic resonance imaging
7. Prior coronary artery bypass graft
8. Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another dialysis unit within 6 months
9. Expected survival < 6 months
10. Allergy to study medications (ISD, HY, adenosine/diprimidole)
11. Active use of sildenafil, vardenafil or tadalafil
12. History of severe aortic stenosis or other cause of LV outflow obstruction
13. Pregnancy, anticipated pregnancy, or breastfeeding, confirmed by serum pregnancy test on the day of PET scan
14. Incarceration
15. Participation in another intervention study
16. Use of monoamine oxidase inhibitors

17. 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
18. Active use of any of the study medications unless participant and physician willing to discontinue prior to enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydralazine/Isorsorbide Dinitrate; 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; 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.; Other Names: Apresoline; Isordil
Active Comparator: Placebo; 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; Placebo titration will mimic titration of active study arm

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: David Charytan, MD, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Mugendi GA, Mutua FM, Natale P, Esterhuizen TM, Strippoli GF. Calcium channel blockers for people with chronic kidney disease requiring dialysis. Cochrane Database Syst Rev. 2020 Oct 1;10(10):CD011064. doi: 10.1002/14651858.CD011064.pub2.

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2017
• Primary Completion (Actual): May 7, 2019
• Study Completion (Actual): May 7, 2019

Study Registration Dates

• First Submitted: August 26, 2014
• First Submitted That Met QC Criteria: August 27, 2014
• First Posted (Estimate): August 29, 2014

Study Record Updates

• Last Update Posted (Actual): April 27, 2021
• Last Update Submitted That Met QC Criteria: March 31, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Cardiovascular Disease; ESRD; hemodialysis; Isosorbide Dinitrate; Hydralazine
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Antihypertensive Agents; Vasodilator Agents; Hydralazine
• Other Study ID Numbers: DK100772-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: deidentified may be shared upon request to the PI

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No