A Phase 2, Pharmacokinetic (PK) Study of 6R-BH4 Alone or 6R-BH4 With Vitamin C in Subjects With Endothelial Dysfunction

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Phase 2 Randomized Open-label 2-Treatment 2-Sequence 2-Period Crossover PK Study to Compare Plasma Concentrations of BH4 in Subjects With Endothelial Dysfunction Following 14 Days of Treatment by 2 Regimens: 6R-BH4 With Vitamin C and 6R-BH4 Alone

Conditions
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Endothelial Dysfunction

Intervention / Treatment
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* Drug: Sapropterin Dihydrochloride
* Drug: Sapropterin Dihydrochloride and Vitamin C


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sapropterin dihydrochloride<br>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. | Drug: Sapropterin Dihydrochloride<br>* 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.<br>* Other names: 6R-BH4;|
| Experimental: Sapropterin dihydrochloride+Vitamin C<br>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. | Drug: Sapropterin Dihydrochloride and Vitamin C<br>* 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.<br>* Other names: 6R-BH4 and Vitamin C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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 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. | 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. | 
| 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. | At Baseline, Day 13 and Day 27 | 
| 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) | At Baseline, Day 13 and Day 27 | 
| 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) | At Baseline, Day 13 and Day 27 | 
| 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. | Up to 56 ± 3 Days. | 
| Change From Baseline in Urinary 8-isoprostane/Creatinine | Biomarkers of endothelial function, oxidative stress, and inflammation as measured by 8-isoprostane. | At Baseline, Day 14 and Day 28 | 
| Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) | Biomarkers of endothelial function, oxidative stress, and inflammation as measured by cyclic guanosine monophosphate (cGMP). | At Baseline, Day 14 and Day 28. | 
| 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 | Baseline, Day 14 and Day 28 | 
| 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 | Baseline, Day 14 and Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BH4, 6R-BH4, BH4 deficiency, sapropterin dihydrochloride, endothelial dysfunction, NO, Hypertension, Nitric Oxide, Vitamin C