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

NCT00532844 | Completed Phase 2 Results

• 1 other identifier: HTN-002
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

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.

Conditions

Endothelial Dysfunction

Keywords

6R-BH4; BH4; BH4 deficiency; sapropterin dihydrochloride; endothelial dysfunction; NO; Hypertension; Nitric Oxide; Vitamin C

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• 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.

• 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.

• 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.

• Change From Baseline in Peripheral Arterial Tonometry (PAT)

  At Baseline, Day 13 and Day 27

• Change From Baseline in Systolic Blood Pressure (SBP)

  At Baseline, Day 13 and Day 27

Study Arms (2)

Sapropterin dihydrochloride

EXPERIMENTAL

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

Sapropterin dihydrochloride+Vitamin C

EXPERIMENTAL

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

Interventions

Sapropterin Dihydrochloride DRUG

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.

Also known as: 6R-BH4

Sapropterin dihydrochloride

Sapropterin Dihydrochloride and Vitamin C DRUG

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.

Also known as: 6R-BH4 and Vitamin C

Sapropterin dihydrochloride+Vitamin C

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (1)

Unknown Facility

Hackensack, New Jersey, United States

Location

Related Links

• BioMarin Pharmaceutical Inc. website

MeSH Terms

Conditions

Phenylketonurias; Hypertension

Interventions

sapropterin; Ascorbic Acid

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates

Results Point of Contact

• Title: Joshua Lilienstein/Medical Director, Global Medical Affairs
• Organization: BioMarin Pharmaceutical Inc.

MEDINFO@bmrn.com

651.523.0310

Study Officials

• Don Nwose, MD

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 18, 2007
• First Posted: September 20, 2007
• Study Start: September 1, 2007
• Primary Completion: November 1, 2008
• Study Completion: March 1, 2009
• Last Updated: May 17, 2021
• Results First Posted: May 17, 2021

Record last verified: 2021-04

Locations

US (1)