Trial Outcomes & Findings for Nitrate Effect on Exercise Capacitance (NCT NCT04297241)

NCT ID: NCT04297241

Last Updated: 2021-09-22

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 20 participants
• Primary outcome timeframe: Baseline and 6 weeks
• Results posted on: 2021-09-22

Participant Flow

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.

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.

Participant milestones

Measure	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.
Overall Study STARTED	20
Overall Study COMPLETED	15
Overall Study NOT COMPLETED	5

Reasons for withdrawal

Measure	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.
Overall Study Withdrawal by Subject	1
Overall Study Adverse Event	1
Overall Study Physician Decision	3

Baseline Characteristics

Nitrate Effect on Exercise Capacitance

Baseline characteristics by cohort

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

PRIMARY outcome

Timeframe: Baseline and 6 weeks

Population: Adverse Events

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).

Outcome measures

Measure	Isosorbide Dinitrate n=20 Participants Determine the number of participants who experience an adverse reaction to the study medication during the study enrollment period.	Isosorbide Dinitrate - Post-therapy Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication liver ultrasound measuring liver stiffness levels.
Number of Participants Who Experience an Adverse Reaction to the Study Medication During the Study Enrollment Period.	16 Participants	—

SECONDARY outcome

Timeframe: Baseline and 6 weeks

Population: Hemodynamic profile

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).

Outcome measures

Measure	Isosorbide Dinitrate n=20 Participants Determine the number of participants who experience an adverse reaction to the study medication during the study enrollment period.	Isosorbide Dinitrate - Post-therapy n=20 Participants Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication liver ultrasound measuring liver stiffness levels.
Effect of Isosorbide Dinitrate on Liver Stiffness Levels	2.3 m/s Standard Deviation 0.4	2.1 m/s Standard Deviation 0.5

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Isosorbide Dinitrate n=20 Participants Determine the number of participants who experience an adverse reaction to the study medication during the study enrollment period.	Isosorbide Dinitrate - Post-therapy n=20 Participants Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication liver ultrasound measuring liver stiffness levels.
Effect of Isosorbide Dinitrate on Central Venous Pressure	22.5 mmHg Standard Deviation 4.5	20.6 mmHg Standard Deviation 2.9

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Isosorbide Dinitrate n=20 Participants Determine the number of participants who experience an adverse reaction to the study medication during the study enrollment period.	Isosorbide Dinitrate - Post-therapy n=20 Participants Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication liver ultrasound measuring liver stiffness levels.
Effect of Isosorbide Dinitrate on Maximal Exercise Capacity VO2 Max	1086.7 mL/min Standard Deviation 312.9	1151.3 mL/min Standard Deviation 301.5

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Isosorbide Dinitrate n=20 Participants Determine the number of participants who experience an adverse reaction to the study medication during the study enrollment period.	Isosorbide Dinitrate - Post-therapy n=20 Participants Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication liver ultrasound measuring liver stiffness levels.
Effect of Isosorbide Dinitrate on Maximal Exercise Capacity Heart Rate Response	156.6 bpm Standard Deviation 26.4	164.7 bpm Standard Deviation 22.1

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Isosorbide Dinitrate n=20 Participants Determine the number of participants who experience an adverse reaction to the study medication during the study enrollment period.	Isosorbide Dinitrate - Post-therapy n=20 Participants Determine effectiveness of study medication on hemodynamic profile by completing baseline and post-study medication liver ultrasound measuring liver stiffness levels.
Effect of Isosorbide Dinitrate on Maximal Exercise Capacity Respiratory Rate Response	1.17 Respiratory Exchange Ratio Standard Deviation 0.09	1.19 Respiratory Exchange Ratio Standard Deviation 0.09

Adverse Events

Isosorbide Dinitrate

Serious events: 1 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Measure	Isosorbide Dinitrate n=20 participants at risk 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.
Cardiac disorders Study Medication Overdose	5.0% 1/20 • Number of events 1 • 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.

Other adverse events

Measure	Isosorbide Dinitrate n=20 participants at risk 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.
Nervous system disorders Headache	80.0% 16/20 • Number of events 23 • 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.
Cardiac disorders Fluttering	5.0% 1/20 • Number of events 1 • 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.
Cardiac disorders Skipped heart beat	5.0% 1/20 • Number of events 1 • 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.
Respiratory, thoracic and mediastinal disorders Sinus infection	5.0% 1/20 • Number of events 1 • 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.
Nervous system disorders Dizziness	10.0% 2/20 • Number of events 2 • 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.
Cardiac disorders Tachycardia	10.0% 2/20 • Number of events 2 • 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.
Nervous system disorders Jittery	5.0% 1/20 • Number of events 1 • 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.
Nervous system disorders Agitation	5.0% 1/20 • Number of events 1 • 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.
Musculoskeletal and connective tissue disorders Arm pain	5.0% 1/20 • Number of events 1 • 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.
Vascular disorders Lightheaded	10.0% 2/20 • Number of events 2 • 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.
Cardiac disorders Burning chest	5.0% 1/20 • Number of events 2 • 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.
Musculoskeletal and connective tissue disorders Pain in extremities	5.0% 1/20 • Number of events 1 • 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.
Musculoskeletal and connective tissue disorders Tingling in extremities	5.0% 1/20 • Number of events 1 • 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.

Additional Information

Mary Banks

Cincinnati Children's Hospital

Phone: 513-636-2147

Email: mary.banks@cchmc.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place