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

NCT00445978 | Completed Phase 2 Results

• 1 other identifier: SCD-001
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 12

Brief Summary

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 sapropterin dihydrochloride 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 sapropterin dihydrochloride, for a total of up to 2 years; The extension phase of this study was terminated.

Conditions

Sickle Cell Disease

Keywords

Sickle Cell Disease; SCD; 6R-BH4; BH4; sapropterin dihydrochloride; endothelial dysfunction; Nitric Oxide; NO

Outcome Measures

Primary Outcomes (1)

• 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 16 weeks

Secondary Outcomes (4)

• Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores

  At Baseline, Week 4, 8, 12 and 16.

• Change From Baseline in the Urine 8-Isoprostane

  At Baseline, Week 4, 8, 12 and 16.

• Change From Baseline in the Urine Spot Albumin to Creatinine Ratio

  At Baseline, Week 4, 8, 12 and 16.

• Change From Baseline in the Tricuspid Regurgitant Velocity (TRV)

  At Baseline, Week 4, 8, 12 and 16.

Study Arms (1)

Sapropterin dihydrochloride

EXPERIMENTAL

2.5, 5, 10, 20 mg/kg/day of sapropterin dihydrochloride 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: Sapropterin Dihydrochloride

Interventions

Sapropterin Dihydrochloride DRUG

Subjects will receive oral, once-daily (for 2.5, 5, 10mg/kg/day doses) or twice-daily (for the 20 mg/kg/day dose) sapropterin dihydrochloride 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. Dosing was with 100 mg tablets and rounded to the nearest whole tablet. Each dose was taken within 1 hour after the morning meal. Subjects may continue in an optional extension phase at the highest tolerated dose for up to a total of 2 years.

Also known as: 6R-BH4

Sapropterin dihydrochloride

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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, desferoxamine) 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.

You may not qualify if:

• 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 sapropterin dihydrochloride or its excipients.

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (12)

Unknown Facility

Washington D.C., District of Columbia, 20060, United States

Location

Unknown Facility

Augusta, Georgia, 30912, United States

Location

Unknown Facility

Savannah, Georgia, 31404, United States

Location

Unknown Facility

Indianapolis, Indiana, 46260, United States

Location

Unknown Facility

Detroit, Michigan, 48201, United States

Location

Unknown Facility

Flint, Michigan, 48503, United States

Location

Unknown Facility

Hackensack, New Jersey, 07601, United States

Location

Unknown Facility

Chapel Hill, North Carolina, 27599, United States

Location

Unknown Facility

Philadelphia, Pennsylvania, 19134, United States

Location

Unknown Facility

Galveston, Texas, 77555, United States

Location

Unknown Facility

Norfolk, Virginia, 23507, United States

Location

Unknown Facility

Richmond, Virginia, 23298, United States

Location

Related Links

• BioMarin Pharmaceutical Inc. website

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

sapropterin

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Limitations and Caveats

The quality of the sickle cell crisis data collected was not adequate to make any conclusions about sapropterin dihydrochloride and sickle cell painful or vaso-occlusive crisis due to selection and reporting bias.

Results Point of Contact

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

MEDINFO@bmrn.com

651.523.0310

Study Officials

• Saba Sile, 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: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2007
• First Posted: March 9, 2007
• Study Start: May 1, 2007
• Primary Completion: August 1, 2008
• Study Completion: June 1, 2009
• Last Updated: February 25, 2021
• Results First Posted: January 28, 2021

Record last verified: 2021-02

Locations

US (12)