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The investigators will investigate the safety and preliminary efficacy of ISDN therapy to reduce venous congestion and improve exercise tolerance in children and adults after the Fontan operation. This will be accomplished by recruiting 15 Fontan physiology patients from the Cincinnati Children's Fontan clinic and University of Kentucky Pediatric Cardiology clinic for the investigation. The investigators will non-invasively measure both central venous pressures at rest and during graded cardiopulmonary exercise testing. In addition the study team will obtain a measurement of liver stiffness before and after a 4-week regimen of ISDN therapy. Patients will be seen twice in clinic, once before and after ISDN therapy, and phone calls will be made to ensure safety, compliance, and make appropriate alterations to medications throughout the study period. Pre- and post-intervention central venous pressure and exercise tolerance will be compared.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Isosorbide Dinitrate | Experimental | Each enrolled participant will be on a titrated dosage of isosorbide dinitrate to determine effectiveness on both primary and secondary outcome measures. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Isosorbide Dinitrate | Drug | All patients will be given a 6 week titration regimen of study medication. Patients will begin at a 5mg dosage and titrate up to 30mg three times per day if each subsequent dose is tolerated. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Experience an Adverse Reaction to the Study Medication During the Study Enrollment Period. | Potential adverse side effects of study medication (isosorbide dinitrate) will be monitored throughout study period. Study medication will be titrated to a maximal dose of 30mg dependent on the patient tolerance. Patient tolerance is defined by frequency of known risk factors to the study medication (headaches, hypotension, and syncope). | Baseline and 6 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Effect of Isosorbide Dinitrate on Liver Stiffness Levels | Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication liver ultrasound measuring liver stiffness levels by sheer wave speed (m/s). | Baseline and 6 weeks |
| Effect of Isosorbide Dinitrate on Central Venous Pressure |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cincinnati Childrens Hospital Medical Center | Cincinnati | Ohio | 45229 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37084132 | Derived | Bigelow AM, Riggs KW, Morales DLS, Opotowsky AR, Lubert AM, Dillman JR, Veldtman GR, Heydarian HC, Trout AT, Cooper DS, Goldstein SL, Chin C, Palermo JJ, Ollberding NJ, Mays WA, Alsaied T. Isosorbide DiNitrate Effect on Hemodynamic Profile, Liver Stiffness, and Exercise Tolerance in Fontan Circulation (The NEET Clinical Trial). Pediatr Cardiol. 2024 Oct;45(7):1389-1397. doi: 10.1007/s00246-023-03156-3. Epub 2023 Apr 21. |
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Each patient came in for a baseline assessment visit. At the end of the baseline visit, they received isosorbide dinitrate, which began at a small dose (5 mg three times daily) and were titrated up to three times daily over 2 weeks. The medication was continued for 4 weeks once the target dose was reached. At the end of 4 weeks, the participants returned for a final visit.
This was a prospective study to evaluate the safety and efficacy of isosorbide dinitrate in children and adults with Fontan physiology in decreasing liver stiffness and lowering exercise related venous pressure responses and increasing exercise tolerance who are ≥ 9 years old. Each patient completed a total of 6 study visits over the course of 2 years.
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| ID | Title | Description |
|---|---|---|
| FG000 | Isosorbide Dinitrate | All patients will have a baseline assessment immediately preceding initiation of isosorbide dinitrate. This will include vitals, urine pregnancy test for all females, blood collection, insertion of a peripheral venous cannula for venous blood pressure during exercise testing, maximal cardiopulmonary exercise testing/Ramp protocol including spirometry, and liver ultrasound to assess for liver stiffness. All patients will then be given a 6 week titration regimen of study medication. Patients will begin at a 5mg dosage and titrate up to 30mg three times per day if each subsequent dose is tolerated. Four follow-up phone calls will take place every 3 days to ensure the patient is tolerating the medication and a medication adjustment will occur as needed. Approximately 4 weeks after study drug administration, participants will return for the same tests/procedures as performed during the baseline visit. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Isosorbide Dinitrate | Isosorbide Dinitrate: This is a prospective study in children and adults with Fontan physiology to see if isosorbide dinitrate will be safely tolerated and improve exercise venous pressure responses, as well as exercise tolerance in Fontan patients. Participants will receive isosorbide dinitrate as a small dose (5 mg three times daily) and titrate up to three times daily over 2 weeks. The medication will continue for 4 weeks once the target dose is reached. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Number of Participants Who Experience an Adverse Reaction to the Study Medication During the Study Enrollment Period. | Potential adverse side effects of study medication (isosorbide dinitrate) will be monitored throughout study period. Study medication will be titrated to a maximal dose of 30mg dependent on the patient tolerance. Patient tolerance is defined by frequency of known risk factors to the study medication (headaches, hypotension, and syncope). | Adverse Events | Posted | Count of Participants | Participants | Baseline and 6 weeks |
|
Isosorbide Dinitrate therapy was initiated at a low dose (e.g. 5 mg three times daily in patients above 50 kg) and increased incrementally over 2 weeks to a goal of 30 mg three times a day. The medication was then continued for approximately 4 weeks once the target dose was achieved for a total of 6 weeks.
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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 | Isosorbide Dinitrate | Isosorbide Dinitrate therapy was initiated at a low dose (e.g. 5 mg three times daily in patients above 50 kg) and increased incrementally over 2 weeks to a goal of 30 mg three times a day. The medication was then continued for approximately 4 weeks once the target dose was achieved for a total of 6 weeks. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Study Medication Overdose | Cardiac disorders | Non-systematic Assessment | Patient understanding of medication dosage calendar was not correct upon completion of initial study visit, therefore patient took a higher dose of medication at the beginning of study participation and needed to restart the study. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mary Banks | Cincinnati Children's Hospital | 513-636-2147 | mary.banks@cchmc.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 | Dec 16, 2020 | Jul 9, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D007548 | Isosorbide Dinitrate |
| ID | Term |
|---|---|
| D007547 | Isosorbide |
| D013012 | Sorbitol |
| D013402 | Sugar Alcohols |
| D000438 | Alcohols |
| D009930 |
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|
Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication maximal exercise tests to measure central venous pressure via IV catheter insertion |
| Baseline and 6 weeks |
| Effect of Isosorbide Dinitrate on Maximal Exercise Capacity VO2 Max | Obtain estimates of the effect the study medication has on maximal exercise test VO2 max performance in Fontan patients by study participants performing a maximal ramp exercise test on a stationary bike. | Baseline and 6 weeks |
| Effect of Isosorbide Dinitrate on Maximal Exercise Capacity Heart Rate Response | Obtain estimates of the effect the study medication has on maximal exercise test heart rate response in Fontan patients by study participants performing a maximal ramp exercise test on a stationary bike. | Baseline and 6 weeks |
| Effect of Isosorbide Dinitrate on Maximal Exercise Capacity Respiratory Rate Response | Obtain estimates of the effect the study medication has on maximal exercise test respiratory rate response in Fontan patients by study participants performing a maximal ramp exercise test on a stationary bike. | Baseline and 6 weeks |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|
| Participants |
|
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| Secondary | Effect of Isosorbide Dinitrate on Liver Stiffness Levels | Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication liver ultrasound measuring liver stiffness levels by sheer wave speed (m/s). | Hemodynamic profile | Posted | Median | Standard Deviation | m/s | Baseline and 6 weeks |
|
|
|
| Secondary | Effect of Isosorbide Dinitrate on Central Venous Pressure | Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication maximal exercise tests to measure central venous pressure via IV catheter insertion | Posted | Median | Standard Deviation | mmHg | Baseline and 6 weeks |
|
|
|
| Secondary | Effect of Isosorbide Dinitrate on Maximal Exercise Capacity VO2 Max | Obtain estimates of the effect the study medication has on maximal exercise test VO2 max performance in Fontan patients by study participants performing a maximal ramp exercise test on a stationary bike. | Posted | Median | Standard Deviation | mL/min | Baseline and 6 weeks |
|
|
|
| Secondary | Effect of Isosorbide Dinitrate on Maximal Exercise Capacity Heart Rate Response | Obtain estimates of the effect the study medication has on maximal exercise test heart rate response in Fontan patients by study participants performing a maximal ramp exercise test on a stationary bike. | Posted | Median | Standard Deviation | bpm | Baseline and 6 weeks |
|
|
|
| Secondary | Effect of Isosorbide Dinitrate on Maximal Exercise Capacity Respiratory Rate Response | Obtain estimates of the effect the study medication has on maximal exercise test respiratory rate response in Fontan patients by study participants performing a maximal ramp exercise test on a stationary bike. | Posted | Median | Standard Deviation | Respiratory Exchange Ratio | Baseline and 6 weeks |
|
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| 0 |
| 20 |
| 1 |
| 20 |
| 16 |
| 20 |
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| Fluttering | Cardiac disorders | Non-systematic Assessment |
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| Skipped heart beat | Cardiac disorders | Non-systematic Assessment |
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| Sinus infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | Non-systematic Assessment |
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| Tachycardia | Cardiac disorders | Non-systematic Assessment |
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| Jittery | Nervous system disorders | Non-systematic Assessment |
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| Agitation | Nervous system disorders | Non-systematic Assessment |
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| Arm pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Lightheaded | Vascular disorders | Non-systematic Assessment |
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| Burning chest | Cardiac disorders | Non-systematic Assessment |
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| Pain in extremities | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Tingling in extremities | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
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| Organic Chemicals |
| D002241 | Carbohydrates |