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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Hydralazine/Isorsorbide Dinitrate | Experimental | 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 | Active Comparator | Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hydralazine/Isorsorbide Dinitrate | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | 6 months |
| Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months | Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography | 0 to 6 months |
| Change in E' on TDI Echo From 0-6 Months | Co-primary efficacy measure measured on Tissue Doppler Echocardiography | 0 to 6 months |
| Reduction in Drug Dose or Discontinuation of Study Drug | Primary Tolerability measure | 0 to 6 months |
| Number of Patients Completing Study From 0 to 6 Months | Primary Feasibility Measure | 0 to 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 0 to 6 months |
| Change in LVMI |
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Inclusion Criteria
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
Active use of any of the study medications unless participant and physician willing to discontinue prior to enrollment.
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| Name | Affiliation | Role |
|---|---|---|
| David Charytan, MD | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham & Women's Hospital | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33000470 | Derived | 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. |
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deidentified may be shared upon request to the PI
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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) | intent to treat | Posted | Count of Participants | Participants | 6 months |
|
6 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| nausea | Gastrointestinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| diarrhea | Gastrointestinal disorders | Systematic Assessment |
small study. unbalanced randomization
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| David Charytan | New York University Medical Center | (646) 501-9086 | david.charytan@nyulangone.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 13, 2018 | Mar 3, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D007676 | Kidney Failure, Chronic |
| D002318 | Cardiovascular Diseases |
| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
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| ID | Term |
|---|---|
| D006830 | Hydralazine |
| D007548 | Isosorbide Dinitrate |
| ID | Term |
|---|---|
| D010793 | Phthalazines |
| D011724 | Pyridazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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|
|
| Placebo | Drug | Placebo titration will mimic titration of active study arm |
|
Change in left ventricular mass index between baseline and 6 months.
| 0 to 6 months |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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 |
|
|
|
| Primary | Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months | Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography | intent to treat | Posted | Mean | Standard Deviation | ratio | 0 to 6 months |
|
|
|
|
| Primary | Change in E' on TDI Echo From 0-6 Months | Co-primary efficacy measure measured on Tissue Doppler Echocardiography | intent to treat | Posted | Mean | Standard Deviation | cm/s | 0 to 6 months |
|
|
|
|
| Primary | Reduction in Drug Dose or Discontinuation of Study Drug | Primary Tolerability measure | intent to treat | Posted | Count of Participants | Participants | 0 to 6 months |
|
|
|
| Primary | Number of Patients Completing Study From 0 to 6 Months | Primary Feasibility Measure | Posted | Count of Participants | Participants | 0 to 6 months |
|
|
|
| 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 | Not done-data. samples not analyzed due to lack of additional funding. | Posted | 0 to 6 months |
|
|
| Secondary | Change in LVMI | Change in left ventricular mass index between baseline and 6 months. | Posted | Mean | Standard Deviation | g/m2 | 0 to 6 months |
|
|
|
|
| 0 |
| 7 |
| 5 |
| 7 |
| 7 |
| 7 |
| EG001 | 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 | 0 | 10 | 3 | 10 | 10 | 10 |
| vomitting | Gastrointestinal disorders | Systematic Assessment |
|
| cv hospitalization | Cardiac disorders | Systematic Assessment |
|
| fall | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| av fisula thrombosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| gi bleeding | Gastrointestinal disorders | Non-systematic Assessment |
|
| headache | Gastrointestinal disorders | Systematic Assessment |
|
| vomitting | Gastrointestinal disorders | Systematic Assessment |
|
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| D052776 |
| Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007547 |
| Isosorbide |
| D013012 | Sorbitol |
| D013402 | Sugar Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D002241 | Carbohydrates |