Single Ventricle Heart Disease
Conditions
Keywords
Fontan, Ultrasound Shear Wave Elastography, Magnetic Resonance Imaging Elastography
Brief summary
A study to evaluate the efficacy of MZ101 therapy in reducing liver stiffness.
Detailed description
This is open-label, long-term prospective study in a cohort of Fontan subjects taking drug daily for one year. The study will determine the scope of hepatic stiffness in the cohort by ultrasound and magnetic resonance imaging elastography and evaluate MZ101 pharmacotherapy as a potentially efficacious treatment to reduce liver stiffness.
Interventions
DRUGUdenafil
Open-label extension with Udenafil 87.5 mg BID treatment for 52 weeks.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Mezzion Pharma Co. Ltd
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Enrollment in on-going Phase 3 Open-Label Safety Study 2. Informed assent from subject, informed consent from parent/legal guardian as appropriate
Exclusion criteria
1. Non-enrollment in the on-going Phase 3 Open-Label Study 2. Subjects with contra-indications for MRI (these subjects will be excluded from the MRI component of this study) 3. Other exclusionary criteria will match those used for the Open-Label Safety Study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Ultrasound Shear Wave Elastography | 52 weeks | Liver stiffness was measured at baseline and 52 weeks using Ultrasound Shear Wave Elastography (USWE) separately in Udenafil Continuation (U+) and Udenafil Naive (U-) groups. A decrease in value indicates a decrease in liver stiffness. |
| Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Magnetic Resonance Elastography | 52 weeks | Liver stiffness was measured at baseline and 52 weeks using Magnetic Resonance Elastography (MRE) separately in Udenafil Continuation (U+) and Udenafil Naive (U-) groups. A decrease in value indicates a decrease in liver stiffness. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Udenafil 87.5 mg BID on Enhanced Liver Fibrosis (ELF) Score After 52 Weeks of Treatment | 52 weeks | Overall ELF score. ELF score is based on the serum levels of hyaluronic acid (HA), amino-terminal propeptide of type III collagen (PIIINP), and tissue inhibitor of metalloproteinase-1 (TIMP-1), and calculated using the following formula: ELF score= 2.494+0.846 In(CHA)+0.391 In(CPIIINP)+0.391 In(CTIMP-1). The levels of each component were as assessed individually and as part of the calculated ELF score as continuous variables. The normal range in healthy subjects ≤20 years of age is 6.9 - 8.8. Correlations between ELF and the degree of liver fibrosis have not been established in patients with Fontan circulation, however, a decrease in ELF score is associated with improved liver health in other disease states. |
| Effect of Udenafil 87.5 mg BID on Brain Natriuretic Peptide After 52 Weeks of Treatment | 52 weeks | Brain Natriuretic Peptide (BNP) was measured at baseline and 52 weeks of treatment. BNP is a biomarker of overall cardiac function across a variety of disease states. A decrease in value is associated with improved cardiac function. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Udenafil Continuation (U+) Subset of subjects on Open-label extension study with Udenafil 87.5 mg BID treatment for 52 weeks, who received active Udenafil 87.5 mg BID treatment in FUEL study prior to enrolling to this study (FALD). | 36 |
| Udenafil Naive (-) Subset of subjects on Open-label extension study with Udenafil 87.5 mg BID treatment for 52 weeks, who received Placebo BID treatment in FUEL study prior to enrolling to this study (FALD). | 52 |
| Total | 88 |
Baseline characteristics
| Characteristic | Udenafil Continuation (U+) | Udenafil Naive (-) | Total |
|---|---|---|---|
| Age, Customized | 15.80 years STANDARD_DEVIATION 1.992 | 15.16 years STANDARD_DEVIATION 1.961 | 15.4 years STANDARD_DEVIATION 2 |
| Body Mass Index (BMI) | 21.9 kilograms per meter squared STANDARD_DEVIATION 4.552 | 21.4 kilograms per meter squared STANDARD_DEVIATION 4.174 | 21.6 kilograms per meter squared STANDARD_DEVIATION 4.314 |
| Brain Natriuretic Peptide (BNP) | 16.89 pg/ml STANDARD_DEVIATION 13.726 | 17.20 pg/ml STANDARD_DEVIATION 13.428 | 17.07 pg/ml STANDARD_DEVIATION 13.464 |
| Enhanced Liver Fibrosis (ELF) | 10.58 score on a scale STANDARD_DEVIATION 0.915 | 10.45 score on a scale STANDARD_DEVIATION 0.853 | 10.50 score on a scale STANDARD_DEVIATION 0.877 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 48 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Height | 162.08 cm STANDARD_DEVIATION 10.277 | 164.89 cm STANDARD_DEVIATION 8.936 | 163.74 cm STANDARD_DEVIATION 9.552 |
| Liver Stiffness by Magnetic Resonance Elastography (MRE) | 5.26 KiloPascal (kPa) STANDARD_DEVIATION 0.927 | 5.26 KiloPascal (kPa) STANDARD_DEVIATION 1.453 | 5.26 KiloPascal (kPa) STANDARD_DEVIATION 1.173 |
| Liver Stiffness by Ultrasound Shear Wave Elastography (USWE) | 1.91 meters/sec STANDARD_DEVIATION 0.38 | 2.02 meters/sec STANDARD_DEVIATION 0.45 | 1.97 meters/sec STANDARD_DEVIATION 0.422 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 32 Participants | 43 Participants | 75 Participants |
| Sex: Female, Male Female | 13 Participants | 19 Participants | 32 Participants |
| Sex: Female, Male Male | 23 Participants | 33 Participants | 56 Participants |
| Weight | 57.48 Kg STANDARD_DEVIATION 13.078 | 58.42 Kg STANDARD_DEVIATION 13.238 | 58.03 Kg STANDARD_DEVIATION 13.105 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 0 |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Magnetic Resonance Elastography
Liver stiffness was measured at baseline and 52 weeks using Magnetic Resonance Elastography (MRE) separately in Udenafil Continuation (U+) and Udenafil Naive (U-) groups. A decrease in value indicates a decrease in liver stiffness.
Time frame: 52 weeks
Population: Only participants with paired data points were included in the analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Udenafil Continuation (U+) | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Magnetic Resonance Elastography | Baseline | 5.26 kiloPascal (kPa) | Standard Deviation 0.927 |
| Udenafil Continuation (U+) | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Magnetic Resonance Elastography | Week 52 | 4.95 kiloPascal (kPa) | Standard Deviation 1.08 |
| Udenafil Naive (U-) | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Magnetic Resonance Elastography | Baseline | 5.26 kiloPascal (kPa) | Standard Deviation 1.453 |
| Udenafil Naive (U-) | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Magnetic Resonance Elastography | Week 52 | 5.50 kiloPascal (kPa) | Standard Deviation 1.55 |
| Total Udenafil | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Magnetic Resonance Elastography | Baseline | 5.26 kiloPascal (kPa) | Standard Deviation 1.173 |
| Total Udenafil | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Magnetic Resonance Elastography | Week 52 | 5.20 kiloPascal (kPa) | Standard Deviation 1.322 |
Primary
Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Ultrasound Shear Wave Elastography
Liver stiffness was measured at baseline and 52 weeks using Ultrasound Shear Wave Elastography (USWE) separately in Udenafil Continuation (U+) and Udenafil Naive (U-) groups. A decrease in value indicates a decrease in liver stiffness.
Time frame: 52 weeks
Population: Only participants with paired data points were included in the analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Udenafil Continuation (U+) | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Ultrasound Shear Wave Elastography | Week 52 | 1.86 meters per second | Standard Deviation 0.288 |
| Udenafil Continuation (U+) | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Ultrasound Shear Wave Elastography | Baseline | 1.91 meters per second | Standard Deviation 0.38 |
| Udenafil Naive (U-) | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Ultrasound Shear Wave Elastography | Baseline | 2.02 meters per second | Standard Deviation 0.45 |
| Udenafil Naive (U-) | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Ultrasound Shear Wave Elastography | Week 52 | 1.96 meters per second | Standard Deviation 0.349 |
| Total Udenafil | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Ultrasound Shear Wave Elastography | Baseline | 1.97 meters per second | Standard Deviation 0.422 |
| Total Udenafil | Effect of Udenafil 87.5 mg BID Treatment on Liver Stiffness in Udenafil Continuation and Naive Groups After 52 Weeks, as Determined by Ultrasound Shear Wave Elastography | Week 52 | 1.92 meters per second | Standard Deviation 0.325 |
Secondary
Effect of Udenafil 87.5 mg BID on Brain Natriuretic Peptide After 52 Weeks of Treatment
Brain Natriuretic Peptide (BNP) was measured at baseline and 52 weeks of treatment. BNP is a biomarker of overall cardiac function across a variety of disease states. A decrease in value is associated with improved cardiac function.
Time frame: 52 weeks
Population: Only participants with paired data points were included in the analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Udenafil Continuation (U+) | Effect of Udenafil 87.5 mg BID on Brain Natriuretic Peptide After 52 Weeks of Treatment | Baseline | 16.89 pg/ml | Standard Deviation 13.726 |
| Udenafil Continuation (U+) | Effect of Udenafil 87.5 mg BID on Brain Natriuretic Peptide After 52 Weeks of Treatment | Week 52 | 20.31 pg/ml | Standard Deviation 18.336 |
| Udenafil Naive (U-) | Effect of Udenafil 87.5 mg BID on Brain Natriuretic Peptide After 52 Weeks of Treatment | Baseline | 17.20 pg/ml | Standard Deviation 13.428 |
| Udenafil Naive (U-) | Effect of Udenafil 87.5 mg BID on Brain Natriuretic Peptide After 52 Weeks of Treatment | Week 52 | 20.78 pg/ml | Standard Deviation 19.165 |
| Total Udenafil | Effect of Udenafil 87.5 mg BID on Brain Natriuretic Peptide After 52 Weeks of Treatment | Baseline | 17.07 pg/ml | Standard Deviation 13.464 |
| Total Udenafil | Effect of Udenafil 87.5 mg BID on Brain Natriuretic Peptide After 52 Weeks of Treatment | Week 52 | 20.59 pg/ml | Standard Deviation 18.698 |
Secondary
Effect of Udenafil 87.5 mg BID on Enhanced Liver Fibrosis (ELF) Score After 52 Weeks of Treatment
Overall ELF score. ELF score is based on the serum levels of hyaluronic acid (HA), amino-terminal propeptide of type III collagen (PIIINP), and tissue inhibitor of metalloproteinase-1 (TIMP-1), and calculated using the following formula: ELF score= 2.494+0.846 In(CHA)+0.391 In(CPIIINP)+0.391 In(CTIMP-1). The levels of each component were as assessed individually and as part of the calculated ELF score as continuous variables. The normal range in healthy subjects ≤20 years of age is 6.9 - 8.8. Correlations between ELF and the degree of liver fibrosis have not been established in patients with Fontan circulation, however, a decrease in ELF score is associated with improved liver health in other disease states.
Time frame: 52 weeks
Population: Only participants with paired data points were included in the analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Udenafil Continuation (U+) | Effect of Udenafil 87.5 mg BID on Enhanced Liver Fibrosis (ELF) Score After 52 Weeks of Treatment | Baseline | 10.58 score on a scale | Standard Deviation 0.915 |
| Udenafil Continuation (U+) | Effect of Udenafil 87.5 mg BID on Enhanced Liver Fibrosis (ELF) Score After 52 Weeks of Treatment | Week 52 | 9.72 score on a scale | Standard Deviation 0.818 |
| Udenafil Naive (U-) | Effect of Udenafil 87.5 mg BID on Enhanced Liver Fibrosis (ELF) Score After 52 Weeks of Treatment | Baseline | 10.45 score on a scale | Standard Deviation 0.853 |
| Udenafil Naive (U-) | Effect of Udenafil 87.5 mg BID on Enhanced Liver Fibrosis (ELF) Score After 52 Weeks of Treatment | Week 52 | 9.79 score on a scale | Standard Deviation 0.75 |
| Total Udenafil | Effect of Udenafil 87.5 mg BID on Enhanced Liver Fibrosis (ELF) Score After 52 Weeks of Treatment | Baseline | 10.50 score on a scale | Standard Deviation 0.877 |
| Total Udenafil | Effect of Udenafil 87.5 mg BID on Enhanced Liver Fibrosis (ELF) Score After 52 Weeks of Treatment | Week 52 | 9.76 score on a scale | Standard Deviation 0.776 |