A Phase 2 Study of the Effects of 6R-BH4 in Subjects With Sickle Cell Disease
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Intervention: Sapropterin Dihydrochloride
Intervention description: 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.
Intervention MeSH terms: Verapamil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 15 Years
Healthy volunteers: No
Keywords: Sickle Cell Disease; SCD; 6R-BH4; BH4; sapropterin dihydrochloride; endothelial dysfunction; Nitric Oxide; NO

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.
    

Eligibility criteria:

        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, 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.

        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 sapropterin dihydrochloride 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.