Nitrate Effect on Exercise Capacitance

Nitrate Effect on Exercise Capacitance and Hemodynamic Profile Prior to Fontan Failure

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04297241

Acronym

NEET

Enrollment

Registered

2020-03-05

Start date

2019-12-12

Completion date

2021-05-03

Last updated

2021-09-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fontan

Brief summary

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.

Interventions

DRUGIsosorbide Dinitrate

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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

9 Years to No maximum

Healthy volunteers

Inclusion criteria

* Underlying Fontan physiology * On a stable medication regimen for the past 3 months * Nine years of age or older

Exclusion criteria

* Pregnant or nursing * Prior hospitalization for heart failure in past year * Presence of uncontrolled arrhythmias within the past 6 months * Non-cardiac conditions which significantly limited exercise * Moderate or severe ventricular dysfunction by echocardiogram or cardiac MRI * Currently treated with a phosphodiesterase-5 inhibitor or organic nitrates * Concurrent enrollment in other investigational drug trial * End stage Liver Disease (ESLD)

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants Who Experience an Adverse Reaction to the Study Medication During the Study Enrollment Period.	Baseline and 6 weeks	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).

Secondary

Measure	Time frame	Description
Effect of Isosorbide Dinitrate on Liver Stiffness Levels	Baseline and 6 weeks	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).
Effect of Isosorbide Dinitrate on Central Venous Pressure	Baseline and 6 weeks	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
Effect of Isosorbide Dinitrate on Maximal Exercise Capacity VO2 Max	Baseline and 6 weeks	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.
Effect of Isosorbide Dinitrate on Maximal Exercise Capacity Heart Rate Response	Baseline and 6 weeks	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.
Effect of Isosorbide Dinitrate on Maximal Exercise Capacity Respiratory Rate Response	Baseline and 6 weeks	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.

Countries

United States

Participant flow

Recruitment details

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.

Pre-assignment details

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.

Participants by arm

Arm	Count
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.	20
Total	20

Arm

Count

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.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	1
Overall Study	Physician Decision	3
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Isosorbide Dinitrate
Age, Categorical <=18 years	5 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	15 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	1 Participants
Race (NIH/OMB) Black or African American	1 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	18 Participants
Region of Enrollment United States	20 participants
Sex: Female, Male Female	8 Participants
Sex: Female, Male Male	12 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 20
other Total, other adverse events	16 / 20
serious Total, serious adverse events	1 / 20

Outcome results

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).