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

NCT ID: NCT02228408

Last Updated: 2021-04-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-28
• Study Completion Date: 2019-05-07

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.

Conditions

Chronic Hemodialysis (ESRD)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

Hydralazine/Isorsorbide Dinitrate

Intervention Type: DRUG

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.

Placebo

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

Group Type: ACTIVE_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo titration will mimic titration of active study arm

Interventions

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.

Intervention Type: DRUG

Placebo

Placebo titration will mimic titration of active study arm

Intervention Type: DRUG

Other Intervention Names

Apresoline; Isordil

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

David Charytan M.D.

Assistant Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

David Charytan, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Brigham & Women's Hospital

Boston, Massachusetts, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 33000470 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

DK100772-01

Identifier Type: -

Identifier Source: org_study_id