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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00532844
Recruitment Status : Completed
First Posted : September 20, 2007
Last Update Posted : December 17, 2014
Information provided by (Responsible Party):
BioMarin Pharmaceutical

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: 6R-BH4 with vitamin C and 6R-BH4 alone.

Condition or disease Intervention/treatment Phase
Endothelial Dysfunction Drug: 6R-BH4 (sapropterin dihydrochloride) Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Open-label, 2-Treatment, 2-Sequence, 2-Period Crossover, Pharmacokinetic (PK) Study to Compare the Plasma Concentrations of BH4 in Subjects With Endothelial Dysfunction Following 14 Days of Treatment by Each of 2 Regimens: 6R-BH4 With Vitamin C and 6R-BH4 Alone
Study Start Date : September 2007
Actual Primary Completion Date : November 2008
Actual Study Completion Date : March 2009

Arm Intervention/treatment
Experimental: 6R-BH4
6R-BH4 5 mg/kg BID for 13.5 days
Drug: 6R-BH4 (sapropterin dihydrochloride)
5 mg/kg BID of 6R-BH4 tablets to be administered orally for 13.5 days

Experimental: 6R-BH4 + Vitamin C
6R-BH4 5 mg/kg BID + 500 mg Vitamin C BID for 13.5 days
Drug: 6R-BH4 (sapropterin dihydrochloride)
5 mg/kg BID of 6R-BH4 tablets, plus 500 mg BID of Vitamin C caplets to be administered orally for 13.5 days

Primary Outcome Measures :
  1. Compare plasma BH4 concentrations at the end of each of the 2 treatment regimens in subjects with endothelial dysfunction [ Time Frame: Day 1, Day 14, Day 28 ]

Secondary Outcome Measures :
  1. Comparison of 6R-BH4+vit C versus 6R-BH4 alone in in terms of plasma concentrations of total biopterins, BH2, B and the ratios BH4:BH2, BH4:BH2+B, BH4:B in subjects with endothelial dysfunction [ Time Frame: Day 1, Day 14, Day 28 ]
  2. Efficacy of 6R-BH4+vit C versus 6R-BH4 alone in improving endothelial function in subjects with endothelial dysfunction as measured by PAT [ Time Frame: Day 1, Day 13, Day 27 ]
  3. Efficacy of 6R-BH4+vit C versus 6R-BH4 alone in lowering blood pressure (BP) in subjects with endothelial dysfunction as measured by ABPM [ Time Frame: Day 1, Day 13, Day 27 ]
  4. Safety of 6R-BH4+vit C versus 6R-BH4 alone in subjects with endothelial dysfunction [ Time Frame: Day 1, Day 13, Day 14, Day 27, Day 28 ]

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00532844

United States, New Jersey
Hackensack, New Jersey, United States
Sponsors and Collaborators
BioMarin Pharmaceutical
Study Director: Don Nwose, MD BioMarin Pharmaceutical

Additional Information:
Responsible Party: BioMarin Pharmaceutical Identifier: NCT00532844     History of Changes
Other Study ID Numbers: HTN-002
First Posted: September 20, 2007    Key Record Dates
Last Update Posted: December 17, 2014
Last Verified: April 2009

Keywords provided by BioMarin Pharmaceutical:
BH4 deficiency
sapropterin dihydrochloride
endothelial dysfunction
Nitric Oxide
Vitamin C

Additional relevant MeSH terms:
Ascorbic Acid
Growth Substances
Physiological Effects of Drugs
Molecular Mechanisms of Pharmacological Action
Protective Agents
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Vasodilator Agents