A Phase 2, Pharmacokinetic (PK) Study of 6R-BH4 Alone or 6R-BH4 With Vitamin C in Subjects With Endothelial Dysfunction
Condition: Endothelial Dysfunction
Intervention: Sapropterin Dihydrochloride; Sapropterin Dihydrochloride and Vitamin C
Intervention description: 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.; 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.
Intervention MeSH terms: Vitamins; Ascorbic Acid; Verapamil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 52.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: 6R-BH4; BH4; BH4 deficiency; sapropterin dihydrochloride; endothelial dysfunction; NO; Hypertension; Nitric Oxide; Vitamin C

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.
    

Eligibility criteria:

        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.