Chronic Hemodialysis (ESRD)
Conditions
Keywords
hemodialysis, ESRD, Cardiovascular Disease, Isosorbide Dinitrate, Hydralazine
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.
Interventions
DRUGHydralazine/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.
DRUGPlacebo
Placebo titration will mimic titration of active study arm
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months | 0 to 6 months | Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography |
| Reduction in Drug Dose or Discontinuation of Study Drug | 0 to 6 months | Primary Tolerability measure |
| Number of Patients Completing Study From 0 to 6 Months | 0 to 6 months | Primary Feasibility Measure |
| Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | 6 months | Rate of primary Safety Outcomes(hypotension, serious adverse events, GI events and CV death) |
| Change in E' on TDI Echo From 0-6 Months | 0 to 6 months | Co-primary efficacy measure measured on Tissue Doppler Echocardiography |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in LVMI | 0 to 6 months | Change in left ventricular mass index between baseline and 6 months. |
| Change in Circulating Fibrosis Markers and Angiogenesis Markers | 0 to 6 months | Circulating concentrations of markers such as the carboxy terminal of pro-collagen type 1 or ADMA will be measured |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
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. | 7 |
| Placebo Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.
Placebo: Placebo titration will mimic titration of active study arm | 10 |
| Total | 17 |
Baseline characteristics
| Characteristic | Hydralazine/Isorsorbide Dinitrate | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 62 years | 62 years | 63 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 12 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 13 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 7 participants | 17 participants | 10 participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 12 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 10 |
| other Total, other adverse events | 7 / 7 | 10 / 10 |
| serious Total, serious adverse events | 5 / 7 | 3 / 10 |
Outcome results
Primary
Change in E' on TDI Echo From 0-6 Months
Co-primary efficacy measure measured on Tissue Doppler Echocardiography
Time frame: 0 to 6 months
Population: intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydralazine/Isorsorbide Dinitrate | Change in E' on TDI Echo From 0-6 Months | 0.56 cm/s | Standard Deviation 1.1 |
| Placebo | Change in E' on TDI Echo From 0-6 Months | -0.04 cm/s | Standard Deviation 0.92 |
p-value: 0.34t-test, 2 sided
Primary
Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months
Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography
Time frame: 0 to 6 months
Population: intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydralazine/Isorsorbide Dinitrate | Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months | -0.27 ratio | Standard Deviation 0.23 |
| Placebo | Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months | -0.03 ratio | Standard Deviation 0.46 |
p-value: 0.19t-test, 2 sided
Primary
Number of Patients Completing Study From 0 to 6 Months
Primary Feasibility Measure
Time frame: 0 to 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydralazine/Isorsorbide Dinitrate | Number of Patients Completing Study From 0 to 6 Months | 6 Participants |
| Placebo | Number of Patients Completing Study From 0 to 6 Months | 10 Participants |
Primary
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)
Time frame: 6 months
Population: intent to treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Hydralazine/Isorsorbide Dinitrate | Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | intradialytic hpypotension | 1 Participants |
| Hydralazine/Isorsorbide Dinitrate | Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | SAE | 5 Participants |
| Hydralazine/Isorsorbide Dinitrate | Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | Nausea | 4 Participants |
| Hydralazine/Isorsorbide Dinitrate | Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | CV death rate per patient year | 0 Participants |
| Placebo | Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | CV death rate per patient year | 0 Participants |
| Placebo | Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | intradialytic hpypotension | 6 Participants |
| Placebo | Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | Nausea | 3 Participants |
| Placebo | Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death | SAE | 3 Participants |
p-value: 0.04poisson
Primary
Reduction in Drug Dose or Discontinuation of Study Drug
Primary Tolerability measure
Time frame: 0 to 6 months
Population: intent to treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Hydralazine/Isorsorbide Dinitrate | Reduction in Drug Dose or Discontinuation of Study Drug | discontinuation | 0 Participants |
| Hydralazine/Isorsorbide Dinitrate | Reduction in Drug Dose or Discontinuation of Study Drug | reduction | 2 Participants |
| Placebo | Reduction in Drug Dose or Discontinuation of Study Drug | discontinuation | 0 Participants |
| Placebo | Reduction in Drug Dose or Discontinuation of Study Drug | reduction | 3 Participants |
Secondary
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
Time frame: 0 to 6 months
Population: Not done-data. samples not analyzed due to lack of additional funding.
Secondary
Change in LVMI
Change in left ventricular mass index between baseline and 6 months.
Time frame: 0 to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydralazine/Isorsorbide Dinitrate | Change in LVMI | -10.6 g/m2 | Standard Deviation 8.5 |
| Placebo | Change in LVMI | -8 g/m2 | Standard Deviation 11.1 |
p-value: 0.62t-test, 2 sided