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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02228408
Recruitment Status : Active, not recruiting
First Posted : August 29, 2014
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
David Charytan M.D., Brigham and Women's Hospital

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.


Condition or disease Intervention/treatment Phase
Chronic Hemodialysis (ESRD) Drug: Hydralazine/Isorsorbide Dinitrate Drug: Placebo Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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
Actual Study Start Date : August 28, 2017
Estimated Primary Completion Date : April 15, 2019
Estimated Study Completion Date : May 15, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dialysis

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




Primary Outcome Measures :
  1. Rate of hypotension, serious adverse events, gi events and cardiovascular death [ Time Frame: 6 months ]
    Primary Safety Outcomes

  2. Efficacy-Change in coronary flow reserve (CFR) from 0-6 months [ Time Frame: 0 to 6 months ]
    Primary Efficacy Measure

  3. Change in E' on TDI Echo from 0-6 months [ Time Frame: 0 to 6 months ]
    Co-primary efficacy measure

  4. Reduction in drug dose or discontinuation of study drug [ Time Frame: 0 to 6 months ]
    Primary Tolerability measure

  5. Number of patients completing study from 0 to 6 months [ Time Frame: 0 to 6 months ]
    Primary Feasibility Measure


Secondary Outcome Measures :
  1. Change in circulating fibrosis markers and angiogenesis markers [ Time Frame: 0 to 6 months ]
    Circulating concentrations of markers such as the carboxy terminal of pro-collagen type 1 or ADMA will be measured

  2. Change in LVMI [ Time Frame: 0 to 6 months ]
    Change in left ventricular mass between baseline and 6 months. Tolerability will be assessed on the basis of whether participants can continue the assigned dose throughout the entire treatment period. Any reduction in dose of study medication will be considered a failure of primary tolerability.


Other Outcome Measures:
  1. Left Ventricular Mass Index [ Time Frame: 0-6 months ]
    Change between baseline and 26 weeks in left ventricular mass index (LVMI)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02228408


Locations
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United States, Massachusetts
Brigham & Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
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Principal Investigator: David Charytan, MD Brigham and Women's Hospital

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Responsible Party: David Charytan M.D., Assistant Professor of Medicine, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT02228408     History of Changes
Other Study ID Numbers: DK100772-01
First Posted: August 29, 2014    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: deidentified may be shared upon request to the PI

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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
Keywords provided by David Charytan M.D., Brigham and Women's Hospital:
hemodialysis
ESRD
Cardiovascular Disease
Isosorbide Dinitrate
Hydralazine
Additional relevant MeSH terms:
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Kidney Failure, Chronic
Renal Insufficiency, Chronic
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Hydralazine
Isosorbide
Isosorbide Dinitrate
Isosorbide-5-mononitrate
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Vasodilator Agents
Nitric Oxide Donors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents