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A Phase 2 Study of the Effects of 6R-BH4 in Subjects With Sickle Cell Disease

This study has been completed.
Information provided by (Responsible Party):
BioMarin Pharmaceutical Identifier:
First received: March 7, 2007
Last updated: September 4, 2014
Last verified: September 2014
This Phase 2a, multicenter, open-label, dose-escalation study is designed to assess the safety and biologic activity of daily oral administration of 4 escalating doses of 6R-BH4 over 16 weeks in subjects with sickle cell disease. During an optional extension phase, the study will assess the safety, tolerability, and efficacy of extended treatment with 6R-BH4, for a total of up to 2 years.

Condition Intervention Phase
Sickle Cell Disease Drug: 6R-BH4 (sapropterin dihydrochloride) Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2a, Multicenter, Open-label, Dose-escalation Study to Evaluate the Safety, Tolerability, and Efficacy of 6R-BH4 in Subjects With Sickle Cell Disease

Resource links provided by NLM:

Further study details as provided by BioMarin Pharmaceutical:

Primary Outcome Measures:
  • To evaluate the safety of oral 6R-BH4 administered in escalating doses to subjects with sickle cell disease (SCD) [ Time Frame: Baseline, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 104 ]

Secondary Outcome Measures:
  • To evaluate changes in physiological and biochemical markers of endothelial function in subjects with SCD receiving escalating doses of oral 6R-BH4 [ Time Frame: Baseline, Week 4, 8, 12, 16, 32, 48, 64, 80, 96 ]
  • Tertiary Outcome: To evaluate changes in clinical measures of SCD in subjects receiving oral 6R-BH4 for up to 2 years [ Time Frame: Baseline, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 104 ]
  • Tertiary Outcome: To evaluate changes in the 6-minute walk (6MW) test in subjects receiving oral 6R-BH4 for up to 2 years [ Time Frame: Baseline, Week, 4, 8, 12, 16, 32, 48, 64, 80, 96 ]

Estimated Enrollment: 40
Study Start Date: April 2007
Study Completion Date: June 2009
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 6R-BH4
2.5, 5, 10, 20 mg/kg/day of 6R-BH4 during a 16-week dose escalation phase, with dose levels increasing within subjects every 4 weeks, with an optional extension phase at the highest tolerated dose for up to a total of 2 years.
Drug: 6R-BH4 (sapropterin dihydrochloride)
Subjects will receive oral, once-daily (for 2.5, 5, 10mg/kg/day doses) or twice-daily (for the 20 mg/kg/day dose) of 6R-BH4 during a 16-week dose escalation phase, with dose levels increasing within subjects every 4 weeks as follows: 2.5, 5, 10, and 20 mg/kg/day. Subjects may continue in an optional extension phase at the highest tolerated dose for up to a total of 2 years.


Ages Eligible for Study:   15 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Diagnosis of SCD, as confirmed by hemoglobin electrophoresis.
  • At least 15 years of age.
  • Dosage of medication(s) used to treat cardiac disease, hypertension (eg, calcium-channel blockers), elevated cholesterol, iron overload (eg, desferoximine) and type 2 diabetes must be unchanged for at least 30 days prior to Screening.
  • Willing and able to provide written, signed informed consent, or in the case of subjects under the age of 18 years, provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures.
  • Willing and able to comply with all study procedures.
  • 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 menopausal for at least 2 years, or had a tubal ligation at least 1 year prior to Screening, or who have had a total hysterectomy.

Exclusion Criteria:

  • Requires chronic hypertransfusion therapy.
  • Sickle cell crisis during the 30 days prior to Screening.
  • Myocardial infarction, cerebral vascular accident, or pulmonary embolism during the 6 months prior to Screening.
  • History of bone marrow or hematopoietic stem cell transplantation.
  • Hepatic dysfunction (alanine aminotransferase [ALT][SGPT] > 2 times the upper limit of normal [ULN]).
  • Renal dysfunction with serum creatinine > 1.5 mg/dL.
  • On outpatient oxygen therapy, or continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) therapy.
  • Uncontrolled hypertension (defined as blood pressure > 135/85 mm Hg) at Screening.
  • History of chronic symptomatic hypotension.
  • Concurrent disease or condition that would interfere with study participation or safety, including, but not limited to: bleeding disorders, history of syncope or vertigo, severe gastroesophageal reflux disease (GERD), arrhythmia, organ transplant, organ failure, type 1 diabetes mellitus (subjects with type 2 diabetes are allowed), or serious neurological disorders (including seizures).
  • Hydroxyurea therapy during the 3 months prior to Screening or anticipated need for hydroxyurea during the course of the study.
  • Treatment with any phosphodiesterase (PDE) 5 inhibitor (Viagra®, Cialis®, Levitra® or Revatio™), any PDE 3 inhibitor (eg, cilostazol, milrinone, or vesnarinone), pentoxifylline (Trental®), nitrate/nitrite-based vasodilators, bosentan (Tracleer®), L-arginine, levodopa, or dietary supplements containing L-arginine or gingko biloba within 30 days prior to Screening, or anticipated need for treatment with any of these agents during the course of the study.
  • Requirement for concomitant treatment with any drug known to inhibit folate metabolism (eg, methotrexate).
  • Previous treatment with vascular endothelial growth factor (VEGF) or VEGF inhibitors.
  • Has known hypersensitivity to 6R-BH4 or its excipients.
  • Use of any investigational product, device, or any formulation of BH4 within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
  • 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 Investigator, places the subject at high risk of poor treatment compliance or of not completing the study.
  Contacts and Locations
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Please refer to this study by its identifier: NCT00445978

United States, District of Columbia
Washington, District of Columbia, United States
United States, Georgia
Augusta, Georgia, United States
Savannah, Georgia, United States
United States, Indiana
Indianapolis, Indiana, United States
United States, Michigan
Detroit, Michigan, United States
Flint, Michigan, United States
United States, New Jersey
Hackensack, New Jersey, United States
United States, North Carolina
Chapel Hill, North Carolina, United States
United States, Pennsylvania
Philadelphia, Pennsylvania, United States
United States, Texas
Galveston, Texas, United States
United States, Virginia
Norfolk, Virginia, United States
Richmond, Virginia, United States
Sponsors and Collaborators
BioMarin Pharmaceutical
Study Director: Saba Sile, MD BioMarin Pharmaceutical
  More Information

Additional Information:
Responsible Party: BioMarin Pharmaceutical Identifier: NCT00445978     History of Changes
Other Study ID Numbers: SCD-001
Study First Received: March 7, 2007
Last Updated: September 4, 2014

Keywords provided by BioMarin Pharmaceutical:
Sickle Cell Disease
sapropterin dihydrochloride
endothelial dysfunction
Nitric Oxide

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents processed this record on August 22, 2017