Clinical trial NCT02228408: Safety and Cardiovascular Efficacy of Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD
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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Hemodialysis (ESRD)
Keywords: hemodialysis
ESRD
Cardiovascular Disease
Isosorbide Dinitrate
Hydralazine
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2014-08-29
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death
timeFrame: 6 months
measure: Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months
timeFrame: 0 to 6 months
measure: Change in E' on TDI Echo From 0-6 Months
timeFrame: 0 to 6 months
measure: Reduction in Drug Dose or Discontinuation of Study Drug
timeFrame: 0 to 6 months
measure: Number of Patients Completing Study From 0 to 6 Months
timeFrame: 0 to 6 months
Secondary outcomes:
measure: Change in Circulating Fibrosis Markers and Angiogenesis Markers
timeFrame: 0 to 6 months
measure: Change in LVMI
timeFrame: 0 to 6 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: David Charytan, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.