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

Primary Purpose

Chronic Hemodialysis (ESRD)

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Hydralazine/Isorsorbide Dinitrate

Placebo

About this trial

This is an interventional prevention trial for Chronic Hemodialysis (ESRD) focused on measuring hemodialysis, ESRD, Cardiovascular Disease, Isosorbide Dinitrate, Hydralazine

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Brigham & Women's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Hydralazine/Isorsorbide Dinitrate

Placebo

Arm Description

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

Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.

Outcomes

Primary Outcome Measures

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)

Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months

Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography

Change in E' on TDI Echo From 0-6 Months

Co-primary efficacy measure measured on Tissue Doppler Echocardiography

Reduction in Drug Dose or Discontinuation of Study Drug

Primary Tolerability measure

Number of Patients Completing Study From 0 to 6 Months

Primary Feasibility Measure

Secondary Outcome Measures

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

Change in LVMI

Change in left ventricular mass index between baseline and 6 months.

Full Information

NCT ID

NCT02228408

First Posted

August 26, 2014

Last Updated

March 31, 2021

Sponsor

Brigham and Women's Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02228408

Brief Title

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

Acronym

HIDE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Completed

Study Start Date

August 28, 2017 (Actual)

Primary Completion Date

May 7, 2019 (Actual)

Study Completion Date

May 7, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Brigham and Women's Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Hemodialysis (ESRD)

Keywords

hemodialysis, ESRD, Cardiovascular Disease, Isosorbide Dinitrate, Hydralazine

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

17 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Hydralazine/Isorsorbide Dinitrate

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo

Arm Type

Active Comparator

Arm Description

Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.

Intervention Type

Drug

Intervention Name(s)

Hydralazine/Isorsorbide Dinitrate

Other Intervention Name(s)

Apresoline, Isordil

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo titration will mimic titration of active study arm

Primary Outcome Measure Information:

Title

Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death

Description

Rate of primary Safety Outcomes(hypotension, serious adverse events, GI events and CV death)

Time Frame

6 months

Title

Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months

Description

Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography

Time Frame

0 to 6 months

Title

Change in E' on TDI Echo From 0-6 Months

Description

Co-primary efficacy measure measured on Tissue Doppler Echocardiography

Time Frame

0 to 6 months

Title

Reduction in Drug Dose or Discontinuation of Study Drug

Description

Primary Tolerability measure

Time Frame

0 to 6 months

Title

Number of Patients Completing Study From 0 to 6 Months

Description

Primary Feasibility Measure

Time Frame

0 to 6 months

Secondary Outcome Measure Information:

Title

Change in Circulating Fibrosis Markers and Angiogenesis Markers

Description

Circulating concentrations of markers such as the carboxy terminal of pro-collagen type 1 or ADMA will be measured

Time Frame

0 to 6 months

Title

Change in LVMI

Description

Change in left ventricular mass index between baseline and 6 months.

Time Frame

0 to 6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David Charytan, MD

Organizational Affiliation

Brigham and Women's Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Brigham & Women's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

deidentified may be shared upon request to the PI

Citations:

PubMed Identifier

33000470

Citation

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.

Results Reference

derived

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

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