The change in exercise capacity (as measured by peak VO2 at maximum exercise effort) from baseline to 26 weeks

Intent to Treat Population

Change in the myocardial performance index (MPI) from baseline to 26 weeks is determined by velocities from blood pool Doppler of the inflow and outflow tract of the dominant ventricle. The measure is the ratio of the sum of isovolumetric contraction time and isovolumetric relaxation time, divided by ventricular ejection time. A lower value is consistent with a more efficient ventricle (better function). A value of zero indicates that there is no isovolumetric contraction or relaxation and, while physiologically implausible, would be consistent with a perfectly efficient ventricle. The mean left ventricular MPI in healthy people without heart disease is approximately 0.35 while the mean right ventricular MPI is approximately 0.1 due to the reduced ventricular afterload of the pulmonary circulation. In general, a decrease in the MPI corresponds to more efficient (better) ventricular function, while an increase in MPI corresponds to less efficient (worse) ventricular function.

This analysis was performed only on participants with paired data. For variety of technical reasons the quality of echocardiographic images were not sufficient to allow for accurate assessment of the MPI in a subset of participants. These reasons include poor acoustic windows and noisy Doppler signal.

Endothelial pulse amplitude tonometry (Endo-PAT) is a technique for the non-invasive assessment of peripheral vascular function. In adults, Endo-PAT has been demonstrated to identify those with coronary artery dysfunction and to correlate with brachial artery reactivity testing. Endo-PAT use in children has been more limited, but has shown excellent reproducibility. Reactive hyperemia index, a measure of the hyperemic response adjusted for baseline blood flow, is a measure of vascular function. A higher value denotes better, or more healthy, vascular (endothelial) function.

This analysis was performed only on participants with paired data. For variety of technical reasons the signal for the reactive hyperemia index was not sufficient to allow for accurate assessment of the index in a subset of participants.

BNP is a hormone produced when the heart is enlarged or has to work harder to pump blood to the body. Higher levels of BNP can be a sign of heart failure.

This analysis was performed on a subset of patients who had analyzable lab samples at both baseline and 26 weeks.

This outcome measures the change in milliliters of oxygen consumption (VO2) per minute at the ventilatory anaerobic threshold (VAT) between Week 26 and Baseline Visits using last observation carried forward (ITT Population). The anaerobic threshold is the period in exercise when metabolism switches from aerobic to anaerobic. This is an useful measure of submaximal exercise capacity particularly in the single ventricle population.

Data from the anaerobic threshold is not calculable for all participants given noise within the data tracings. These data are from the intent to treat (ITT) analyses for all participants for whom a baseline value was calculable.

This outcome measures the change in work (measured in Watts) at the ventilatory anaerobic threshold (VAT) between Week 26 and Baseline Visits using last observation carried forward (ITT Population). The anaerobic threshold is the period in exercise when metabolism switches from aerobic to anaerobic. This is an useful measure of submaximal exercise capacity particularly in the single ventricle population.

Data from the anaerobic threshold is not calculable for all participants given noise within the data tracings. These data are from the intent to treat (ITT) analyses for all participants for whom a baseline value was calculable.

This measure is a ratio of the amount of inspired air required to clear a given volume of CO2 from the circulation at the ventilatory anaerobic threshold (VAT). This measurement is made during exercise stress testing. Decreases in this ratio may reflect an improvement in ventilatory efficiency or an improvement in cardiac function.

Data from the anaerobic threshold is not calculable for all participants given noise within the data tracings. These data are from the intent to treat (ITT) analyses for all participants for whom a baseline value was calculable.

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or the participant did not complete the assessment, but was encouraged to come back to complete Week 26 assessments. Only participants with both a Baseline value and a Week 26 value were included in the analysis.

The amount of air that enters the lungs per minute at maximal exercise effort.

ITT Population. Of note, some participants may not have had baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back to complete Week 26 assessments. Only participants with both a baseline value and a Week 26 value were included in the analysis.

Change in power at maximal exercise effort.

ITT Population. Of note, some participants may not have had baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back to complete Week 26 assessments. Only participants with both a baseline value and a Week 26 value were included in the analysis.

The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis.

The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis.

The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis.

The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis.

The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis.

The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis.

The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis.

The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis.

The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 week. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis.

The PCLQI is a disease-specific measure of health-related quality of life for children and adolescents with congenital or acquired heart disease. The PCQLI score is calculated by adding together the scores from the two subscales: Disease Impact and Psychosocial Impact. Each subscale can score a maximum of 50 points, resulting in a total score with a maximum of 100. Higher scores indicate better perceived health-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value who were aged 8 to 12 were included in the analysis.

The PCLQI is a disease-specific measure of health-related quality of life for children and adolescents with congenital or acquired heart disease. The PCQLI score is calculated by adding together the scores from the two subscales: Disease Impact and Psychosocial Impact. Each subscale can score a maximum of 50 points, resulting in a total score with a maximum of 100. Higher scores indicate better perceived health-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants with both a Baseline and a Week 26 value were included in the analysis. Only parents with participants aged 8-12 were included in the analysis.

The PCLQI is a disease-specific measure of health-related quality of life for children and adolescents with congenital or acquired heart disease. The PCQLI score is calculated by adding together the scores from the two subscales: Disease Impact and Psychosocial Impact. Each subscale can score a maximum of 50 points, resulting in a total score with a maximum of 100. Higher scores indicate better perceived health-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only participants aged 13-18 with both a Baseline and a Week 26 value were included in the analysis.

The PCLQI is a disease-specific measure of health-related quality of life for children and adolescents with congenital or acquired heart disease. The PCQLI score is calculated by adding together the scores from the two subscales: Disease Impact and Psychosocial Impact. Each subscale can score a maximum of 50 points, resulting in a total score with a maximum of 100. Higher scores indicate better perceived health-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).

ITT Population. Of note, some participants may not have had Baseline values due to errors in data capture and/or not completing the assessment, but were encouraged to come back and complete the Week 26 assessments. Only parents of participants aged 13-18 with both a Baseline and a Week 26 value were included in the analysis.