Endothelial Dysfunction
Conditions
Keywords
6R-BH4, BH4, BH4 deficiency, sapropterin dihydrochloride, endothelial dysfunction, NO, Hypertension, Nitric Oxide, Vitamin C
Brief summary
This Phase 2, randomized, open-label, 2-treatment, 2-sequence, 2-period crossover, pharmacokinetic (PK) study will compare plasma concentrations of BH4 in subjects with endothelial dysfunction following 14 days of treatment by each of 2 regimens: sapropterin dihydrochloride with vitamin C and sapropterin dihydrochloride alone.
Detailed description
This was a Phase 2, randomized, open-label, 2-treatment, 2-sequence, 2-period crossover, pharmacokinetic (PK) study designed to compare the plasma concentrations of BH4 in subjects with endothelial dysfunction following 14 days of treatment by each of 2 regimens: sapropterin dihydrochloride with vitamin C and sapropterin dihydrochloride alone. Each subject received each regimen; the 2 treatment groups varied only in the sequence of the 2 regimens. The washout period between treatment regimens comprised the 1 day period between the last dose of study drug under the first regimen and the first dose of study drug under the second regimen (Day 14 morning to Day 15 morning).
Interventions
Sapropterin Dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28.
DRUGSapropterin Dihydrochloride and Vitamin C
Sapropterin Dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures. * Age is ≥ 18 years and ≤ 75 years. * Willing and able to comply with all study procedures. * If currently receiving treatment with or taking any of the following supplements, be willing and able to discontinue taking them throughout the treatment period: * Vit C supplements * Multivitamins containing vit C * Any other dietary supplements, nutraceuticals, or other over- the-counter products containing vit C * Vitamin E-containing supplements * History of cardiovascular disease or cardiovascular risk factors, eg, stable and well-controlled Type 2 diabetes, peripheral arterial disease, obesity, smoking, hypercholesterolemia * Endothelial dysfunction, documented at screening by an abnormal peripheral arterial tonometry (PAT) of ≤ 1.70. * Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study. * Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have been in menopause at least 2 years, or had tubal ligation at least 1 year prior to screening, or who have had total hysterectomy.
Exclusion criteria
* Hypertension secondary to other medical conditions (e.g., renal failure or steroid usage). * Concurrent disease or condition that would interfere with study participation or safety, such as bleeding disorders; history of syncope or vertigo; severe gastroesophageal reflux disease (GERD); heart failure; symptomatic coronary disease; arrhythmia; serious neurologic disorders, including seizures; organ transplant; or organ failure. * Type 2 diabetics that are uncontrolled, unstable, newly diagnosed, or have changed therapy in the last three months and all Type 1 diabetics. * Any severe comorbid condition that would limit life expectancy to \< 6 months. * Serum creatinine \> 2.0 mg/dL, or hepatic enzyme concentrations \> 2 times the upper limit of normal * HIV infection, hepatic cirrhosis, other preexisting liver disease, or positive HIV, Hepatitis B or C test at screening. * Concomitant treatment with: * Drugs known to inhibit folate metabolism (e.g., methotrexate) * Levodopa * A phosphodiesterase (PDE) 5 inhibitor (e.g., Viagra®, Cialis®, Levitra®, or Revatio®) * A PDE 3 inhibitor (e.g., cilostazol, milrinone, or vesnarinone) * Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments. * Myocardial infarction, stroke, or surgery within the last 60 days prior to screening. * History of alcohol and/or drug abuse or a positive alcohol or drug test at screening. * Previous treatment with any formulation of BH4. * Has known hypersensitivity to 6R-BH4 or its excipients. * Pregnant or breastfeeding at screening, or planning to become pregnant (self or partner) at any time during the study. * Any condition that, in the view of the PI, places the subject at high risk of poor treatment compliance or of not completing the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC0-12hrs) of Plasma BH4 Concentration | At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing. | Plasma BH4 concentration area under the curve (AUC0-12 hrs) at the end of each regimen in subjects with endothelial dysfunction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC0-12hours) for Calculated BH4 (From Total Biopterin) | At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing. | Total biopterin concentration area under the curve (AUC0-12hours) at the end of each regimen in subjects with endothelial dysfunction is theoretically the sum of BH4, BH2 and B. Biopterin is the metabolite of BH4 after oxidative conversion of BH4 and BH2 to biopterin. Total biopterin concentrations represent the summation of drug and metabolites: BH4, BH2 and B. The total biopterin concentrations can be converted to BH4 concentration using the conversion factor 2.150. |
| Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone. | At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing. | Ratio of Mean AUC (0-12 hours) for subjects receiving (Sapropterin dihydrochloride + Vitamin C)/ Mean AUC (0-12 hours) for subjects receiving Sapropterin dihydrochloride alone) for BH4, BH2, B, BH4/BH2 Ratio, and BH4 Calculated from Total Biopterin. |
| Change From Baseline in Peripheral Arterial Tonometry (PAT) | At Baseline, Day 13 and Day 27 | PAT measures pulse wave amplitude of the small arteries of the finger as a surrogate to assess endothelial function and arterial stiffness using a finger plethysmographic probe and 5-minute occlusion of the brachial artery. Endothelial dysfunction, a protocol inclusion criteria, is defined by an abnormal PAT of \< or = 1.70. Change is calculated as follows: end time measurement - starting time measurement. |
| Change From Baseline in Systolic Blood Pressure (SBP) | At Baseline, Day 13 and Day 27 | Change is calculated as follows: end time measurement - starting time measurement. Mean daytime systolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) |
| Change From Baseline in Diastolic Blood Pressure (DBP) | At Baseline, Day 13 and Day 27 | Change is calculated as follows: end time measurement - starting time measurement. Mean daytime diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM) |
| Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration | At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing. | Plasma BH2 and B concentration area under the curve (AUC0-12hrs) at the end of each regimen in subjects with endothelial dysfunction. |
| Change From Baseline in Urinary 8-isoprostane/Creatinine | At Baseline, Day 14 and Day 28 | Biomarkers of endothelial function, oxidative stress, and inflammation as measured by 8-isoprostane. |
| Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) | At Baseline, Day 14 and Day 28. | Biomarkers of endothelial function, oxidative stress, and inflammation as measured by cyclic guanosine monophosphate (cGMP). |
| Change in Urinary Albumin to Creatinine Ratio (mg/g) | Baseline, Day 14 and Day 28 | Change in Urinary Albumin to Creatinine Ratio (mg/g) from Baseline to Day 14, Baseline to Day 28, and from Day 14 to Day 28 |
| Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Baseline, Day 14 and Day 28 | Summary of Urinary Albumin to Creatinine Ratio (mg/g) by subjects with ratio \<30 mg/g and subjects with ratios \>=30 mg/g at Baseline, Day 14 and Day 28 |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Up to 56 ± 3 Days. | A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. |
Countries
United States
Participant flow
Recruitment details
This was a single-center study.
Pre-assignment details
A total of 52 subjects were randomized into the study and received study drug. Of these, 4 subjects were enrolled under an earlier version of the protocol that used different eligibility criteria and were monitored according to different data collection procedures. Only the 48 subjects enrolled under the final protocol were included in the analyses.
Participants by arm
| Arm | Count |
|---|---|
| Sapropterin Dihydrochloride 10mg/kg First, Then Sapropterin Dihydrochloride 10mg/kg and Vitamin C Sequence A: Sapropterin dihydrochloride as the first treatment followed by sapropterin dihydrochloride and vitamin C
Treatment Regimen 1: Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14.
Treatment Regimen 2: Sapropterin dihydrochloride 5 mg/kg + 500 mg vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 28
The washout period of 1 day comprised between treatment regimens. | 24 |
| Sapropterin Dihydrochloride 10mg/kg and Vitamin C First, Then Sapropterin Dihydrochloride 10mg/kg Sequence B: Sapropterin dihydrochloride and vitamin C as the first treatment followed by sapropterin dihydrochloride
Treatment Regimen 2: Sapropterin dihydrochloride 5 mg/kg + 500 mg vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14.
Treatment Regimen 1: Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal Day 28.
The washout period of 1 day comprised between treatment regimens. | 24 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period - Day 15 to Day 28 | Adverse Event | 1 | 0 |
| Treatment Period - Day 15 to Day 28 | Personal reasons | 1 | 0 |
| Treatment Period - Day 15 to Day 28 | Pregnancy | 1 | 0 |
| Treatment Period - Day 15 to Day 28 | withdrawal of consent | 1 | 0 |
| Treatment Period - Day 1 to Day 14 | Withdrawal of consent | 0 | 1 |
Baseline characteristics
| Characteristic | Sapropterin Dihydrochloride 10mg/kg First, Then Sapropterin Dihydrochloride 10mg/kg and Vitamin C | Total | Sapropterin Dihydrochloride 10mg/kg and Vitamin C First, Then Sapropterin Dihydrochloride 10mg/kg |
|---|---|---|---|
| Age < 65 Years | 24 Participants | 46 Participants | 22 Participants |
| Age ≥ 65 Years | 0 Participants | 2 Participants | 2 Participants |
| Age, Continuous | 42.7 years STANDARD_DEVIATION 12.1 | 42.9 years STANDARD_DEVIATION 13 | 43.2 years STANDARD_DEVIATION 14 |
| Body Mass Index | 32.33 kg/m^2 STANDARD_DEVIATION 5.62 | 32.39 kg/m^2 STANDARD_DEVIATION 5.6 | 32.45 kg/m^2 STANDARD_DEVIATION 5.7 |
| Ethnicity Hispanic or Latino | 6 Participants | 13 Participants | 7 Participants |
| Ethnicity Not Hispanic or Latino | 18 Participants | 35 Participants | 17 Participants |
| Height | 170.81 cm STANDARD_DEVIATION 8.47 | 171.76 cm STANDARD_DEVIATION 9.21 | 172.71 cm STANDARD_DEVIATION 9.98 |
| Race Black/African American | 13 Participants | 21 Participants | 8 Participants |
| Race Other | 1 Participants | 2 Participants | 1 Participants |
| Race White | 10 Participants | 25 Participants | 15 Participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 16 Participants | 32 Participants | 16 Participants |
| Weight | 95.78 kg STANDARD_DEVIATION 18.36 | 96.29 kg STANDARD_DEVIATION 17.48 | 96.80 kg STANDARD_DEVIATION 16.93 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 0 / 50 |
| other Total, other adverse events | 19 / 49 | 16 / 50 |
| serious Total, serious adverse events | 0 / 49 | 0 / 50 |
Outcome results
Primary
Area Under the Curve (AUC0-12hrs) of Plasma BH4 Concentration
Plasma BH4 concentration area under the curve (AUC0-12 hrs) at the end of each regimen in subjects with endothelial dysfunction.
Time frame: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Population: Intent-to-treat (ITT) Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Area Under the Curve (AUC0-12hrs) of Plasma BH4 Concentration | 633 nM*hr | Standard Deviation 286 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Area Under the Curve (AUC0-12hrs) of Plasma BH4 Concentration | 993 nM*hr | Standard Deviation 545 |
Comparison: To determine if administration of saproprterin dihydrochloride administered with Vitamin C results in higher plasma BH4 concentrations when compared with administration of sapropterin dihydrochloride alone in subjects with endothelial dysfunction. The difference in the plasma BH4 concentration (AUC0-12 hr) between the 2 regimens will be compared using a mixed model with a 0.05 level of significance. The difference is represented as the geometric mean ratio.p-value: <0.00195% CI: [1.2, 1.8]Mixed Models Analysis
Secondary
Area Under the Curve (AUC0-12hours) for Calculated BH4 (From Total Biopterin)
Total biopterin concentration area under the curve (AUC0-12hours) at the end of each regimen in subjects with endothelial dysfunction is theoretically the sum of BH4, BH2 and B. Biopterin is the metabolite of BH4 after oxidative conversion of BH4 and BH2 to biopterin. Total biopterin concentrations represent the summation of drug and metabolites: BH4, BH2 and B. The total biopterin concentrations can be converted to BH4 concentration using the conversion factor 2.150.
Time frame: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Area Under the Curve (AUC0-12hours) for Calculated BH4 (From Total Biopterin) | 440 nM*hr | Standard Deviation 183 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Area Under the Curve (AUC0-12hours) for Calculated BH4 (From Total Biopterin) | 440 nM*hr | Standard Deviation 211 |
Secondary
Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration
Plasma BH2 and B concentration area under the curve (AUC0-12hrs) at the end of each regimen in subjects with endothelial dysfunction.
Time frame: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration | BH2 | 875 nM*hr | Standard Deviation 455 |
| Sapropterin Dihydrochloride 10 mg/kg | Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration | B | 231 nM*hr | Standard Deviation 163 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration | BH2 | 772 nM*hr | Standard Deviation 376 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration | B | 185 nM*hr | Standard Deviation 123 |
Comparison: To determine if administration of saproprterin dihydrochloride administered with Vitamin C results in higher plasma BH2 when compared with administration of sapropterin dihydrochloride alone in subjects with endothelial dysfunction. The difference in the plasma BH2 concentration (AUC0-12 hr) between the 2 regimens will be compared using a mixed model with a 0.05 level of significance. The difference is represented as the geometric mean ratio.p-value: 0.13995% CI: [0.7, 1]Mixed Models Analysis
Comparison: To determine if administration of saproprterin dihydrochloride administered with Vitamin C results in Total B (biopterin) when compared with administration of sapropterin dihydrochloride alone in subjects with endothelial dysfunction. The difference in the Total B (biopterin) concentration (AUC0-12 hr) between the 2 regimens will be compared using a mixed model with a 0.05 level of significance. The difference is represented as the geometric mean ratio.p-value: 0.5795% CI: [0.83, 1.11]Mixed Models Analysis
Secondary
Change From Baseline in Cyclic Guanosine Monophosphate (cGMP)
Biomarkers of endothelial function, oxidative stress, and inflammation as measured by cyclic guanosine monophosphate (cGMP).
Time frame: At Baseline, Day 14 and Day 28.
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) | Baseline | 3.7941 pmol/mL | Standard Deviation 1.1839 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) | Change from Baseline to Day 14 | 0.6278 pmol/mL | Standard Deviation 2.0258 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) | Change from Day 14 to Day 28 | -0.0507 pmol/mL | Standard Deviation 1.1369 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) | Change from Baseline to Day 14 | 0.2088 pmol/mL | Standard Deviation 1.3248 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) | Baseline | 3.8533 pmol/mL | Standard Deviation 1.4658 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) | Change from Day 14 to Day 28 | -0.0078 pmol/mL | Standard Deviation 1.9556 |
Secondary
Change From Baseline in Diastolic Blood Pressure (DBP)
Change is calculated as follows: end time measurement - starting time measurement. Mean daytime diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM)
Time frame: At Baseline, Day 13 and Day 27
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Diastolic Blood Pressure (DBP) | Baseline | 77.32 mm Hg | Standard Deviation 11.05 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Diastolic Blood Pressure (DBP) | Change from Baseline to Day 13 | -2.31 mm Hg | Standard Deviation 6.84 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Diastolic Blood Pressure (DBP) | Change from Day 13 to Day 27 | -2.01 mm Hg | Standard Deviation 6.6 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Diastolic Blood Pressure (DBP) | Baseline | 80.15 mm Hg | Standard Deviation 14.05 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Diastolic Blood Pressure (DBP) | Change from Baseline to Day 13 | 0.45 mm Hg | Standard Deviation 5.31 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Diastolic Blood Pressure (DBP) | Change from Day 13 to Day 27 | 1.23 mm Hg | Standard Deviation 5.21 |
Secondary
Change From Baseline in Peripheral Arterial Tonometry (PAT)
PAT measures pulse wave amplitude of the small arteries of the finger as a surrogate to assess endothelial function and arterial stiffness using a finger plethysmographic probe and 5-minute occlusion of the brachial artery. Endothelial dysfunction, a protocol inclusion criteria, is defined by an abnormal PAT of \< or = 1.70. Change is calculated as follows: end time measurement - starting time measurement.
Time frame: At Baseline, Day 13 and Day 27
Population: ITT population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Day 13 | 1.8509 Ratio | Standard Deviation 0.4677 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Day 27 | 1.9047 Ratio | Standard Deviation 0.4903 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Baseline | 1.5113 Ratio | Standard Deviation 0.1669 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Change from Day 13 to Day 27 | 0.1293 Ratio | Standard Deviation 0.4897 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Change from Baseline to Day 13 | 0.3467 Ratio | Standard Deviation 0.4311 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Change from Day 13 to Day 27 | -0.1641 Ratio | Standard Deviation 0.4294 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Baseline | 1.4859 Ratio | Standard Deviation 0.1437 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Day 13 | 1.7754 Ratio | Standard Deviation 0.376 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Change from Baseline to Day 13 | 0.2902 Ratio | Standard Deviation 0.4329 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Peripheral Arterial Tonometry (PAT) | Day 27 | 1.6482 Ratio | Standard Deviation 0.425 |
Comparison: The raw value of PAT obtained from the first period (baseline to Day 13) will be used to compare the two treatments.p-value: 0.593ANCOVA
Secondary
Change From Baseline in Systolic Blood Pressure (SBP)
Change is calculated as follows: end time measurement - starting time measurement. Mean daytime systolic blood pressure measured by ambulatory blood pressure monitoring (ABPM)
Time frame: At Baseline, Day 13 and Day 27
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) | Baseline | 125.14 mm Hg | Standard Deviation 13.42 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) | Change from Baseline to Day 13 | -3.24 mm Hg | Standard Deviation 8.64 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) | Change from Day 13 to Day 27 | -1.67 mm Hg | Standard Deviation 7.29 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) | Baseline | 131.29 mm Hg | Standard Deviation 13.05 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) | Change from Baseline to Day 13 | -0.10 mm Hg | Standard Deviation 6.53 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) | Change from Day 13 to Day 27 | 3.31 mm Hg | Standard Deviation 6.43 |
Secondary
Change From Baseline in Urinary 8-isoprostane/Creatinine
Biomarkers of endothelial function, oxidative stress, and inflammation as measured by 8-isoprostane.
Time frame: At Baseline, Day 14 and Day 28
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Urinary 8-isoprostane/Creatinine | Baseline | 898.01 pg/mg | Standard Deviation 671.25 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Urinary 8-isoprostane/Creatinine | Change from Baseline to Day 14 | -192.13 pg/mg | Standard Deviation 529.16 |
| Sapropterin Dihydrochloride 10 mg/kg | Change From Baseline in Urinary 8-isoprostane/Creatinine | Change from Day 14 to Day 28 | -117.61 pg/mg | Standard Deviation 472.61 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Urinary 8-isoprostane/Creatinine | Baseline | 992.38 pg/mg | Standard Deviation 569.8 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Urinary 8-isoprostane/Creatinine | Change from Baseline to Day 14 | -31.75 pg/mg | Standard Deviation 664.4 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change From Baseline in Urinary 8-isoprostane/Creatinine | Change from Day 14 to Day 28 | 32.44 pg/mg | Standard Deviation 364.6 |
Secondary
Change in Urinary Albumin to Creatinine Ratio (mg/g)
Change in Urinary Albumin to Creatinine Ratio (mg/g) from Baseline to Day 14, Baseline to Day 28, and from Day 14 to Day 28
Time frame: Baseline, Day 14 and Day 28
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Change in Urinary Albumin to Creatinine Ratio (mg/g) | Baseline | 13.3 mg/g | Standard Deviation 35.7 |
| Sapropterin Dihydrochloride 10 mg/kg | Change in Urinary Albumin to Creatinine Ratio (mg/g) | Change from Baseline to Day 14 | -1.2 mg/g | Standard Deviation 17.9 |
| Sapropterin Dihydrochloride 10 mg/kg | Change in Urinary Albumin to Creatinine Ratio (mg/g) | Change from Day 14 to Day 28 | -2.2 mg/g | Standard Deviation 4.9 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change in Urinary Albumin to Creatinine Ratio (mg/g) | Change from Baseline to Day 14 | 2.7 mg/g | Standard Deviation 18.6 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change in Urinary Albumin to Creatinine Ratio (mg/g) | Baseline | 12.3 mg/g | Standard Deviation 19 |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Change in Urinary Albumin to Creatinine Ratio (mg/g) | Change from Day 14 to Day 28 | 4.9 mg/g | Standard Deviation 10.2 |
Secondary
Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g
Summary of Urinary Albumin to Creatinine Ratio (mg/g) by subjects with ratio \<30 mg/g and subjects with ratios \>=30 mg/g at Baseline, Day 14 and Day 28
Time frame: Baseline, Day 14 and Day 28
Population: ITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Baseline < 30 mg/g | 13 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Baseline >=30 mg/g | 1 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Day 14 < 30 mg/g | 10 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Day 14 >=30 mg/g | 2 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Day 28 < 30 mg/g | 12 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Day 28 >=30 mg/g | 1 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Day 28 < 30 mg/g | 10 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Baseline < 30 mg/g | 16 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Day 14 >=30 mg/g | 1 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Baseline >=30 mg/g | 2 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Day 28 >=30 mg/g | 2 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g | Day 14 < 30 mg/g | 13 Participants |
Secondary
Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration.
Time frame: Up to 56 ± 3 Days.
Population: ITT and Safety Population. Four subjects enrolled in the study before changing from a parallel to a cross over study not reflected in the data table in the Participant Flow module. Two subjects received sapropterin dihydrochloride only and two subjects received sapropterin dihydrichloride + vitamin C only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any treatment-related Serious Adverse Event | 0 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any Adverse Event | 19 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any treatment-related Adverse Event | 16 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any AEs Leading to Study Discontinuation | 1 Participants |
| Sapropterin Dihydrochloride 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any Serious Adverse Event | 0 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any AEs Leading to Study Discontinuation | 0 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any Serious Adverse Event | 0 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any Adverse Event | 16 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any treatment-related Adverse Event | 13 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any treatment-related Serious Adverse Event | 0 Participants |
| Sapropterin Dihydrochloride+Vitamin C 10 mg/kg | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Death | 0 Participants |
Secondary
Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone.
Ratio of Mean AUC (0-12 hours) for subjects receiving (Sapropterin dihydrochloride + Vitamin C)/ Mean AUC (0-12 hours) for subjects receiving Sapropterin dihydrochloride alone) for BH4, BH2, B, BH4/BH2 Ratio, and BH4 Calculated from Total Biopterin.
Time frame: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.
Population: ITT population. AUC (0 to 12 hour) means were calculated for 44 subjects in the Sapropterin dihydrichloride and 43 subjects on Sapropterin dihydrochloride + Vitamin C
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 10 mg/kg | Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone. | BH2 | 0.998 ratio | Standard Deviation 0.577 |
| Sapropterin Dihydrochloride 10 mg/kg | Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone. | B | 1.04 ratio | Standard Deviation 1.1 |
| Sapropterin Dihydrochloride 10 mg/kg | Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone. | Calculated BH4 (from Total Biopterin) | 1.03 ratio | Standard Deviation 0.33 |