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

Study Overview
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Brief Summary
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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.

Detailed Description
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This Phase 2a, multicenter, open-label, dose-escalation study was designed to assess the safety and biological activity of once-daily (or twice-daily [BID], only for the highest dose level) oral administration of 4 escalating doses of sapropterin dihydrochloride to subjects with Sickle Cell Disease (SCD); 32 subjects were enrolled in the dose-escalation phase of this study. Subjects received oral, once daily (for 2.5, 5, and 10 mg/kg/day) or BID (for 20 mg/kg/day) doses of sapropterin dihydrochloride during a 16-week, dose-escalation period, with dose levels increasing within subjects every 4 weeks, as follows: 2.5, 5, 10, and 20 mg/kg/day. At the highest dose level (20 mg/kg/day), the total dose of sapropterin dihydrochloride was divided, half of the tablets taken in the morning within 1 hour after a meal, and half approximately 12 hours later (or BID) within 1 hour after a meal. The extension phase of this study was terminated.

Official Title
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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

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Sapropterin Dihydrochloride


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sapropterin dihydrochloride<br>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<br>* 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.<br>* Other names: 6R-BH4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores | The PAT score was calculated using the ratio between the arterial pulse wave amplitude following a 5-minute arterial occlusion in the forearm to the pre-occlusion value (Reactive Hyperemia Index). A value of </= 1.67 represents an impaired response or endothelial dysfunction. Change in PAT from Baseline to posttreatment visit is calculated by subtracting the Baseline measurement from the posttreatment measurement. | At Baseline, Week 4, 8, 12 and 16. | 
| Change From Baseline in the Urine 8-Isoprostane | Change in urine 8-isoprostane from Baseline to post-treatment visit is calculated by subtracting the Baseline measurement from the post-treatment measurement. This outcome was used to assess change in oxidative stress. | At Baseline, Week 4, 8, 12 and 16. | 
| Change From Baseline in the Urine Spot Albumin to Creatinine Ratio | Change in Urine Albumin to Creatinine Ratio from Baseline to post-treatment visit is calculated by subtracting the Baseline measurement from the post-treatment measurement. This outcome was used to assess change in renal function. | At Baseline, Week 4, 8, 12 and 16. | 
| Change From Baseline in the Tricuspid Regurgitant Velocity (TRV) | Change in tricuspid regurgitant velocity (TRV) from Baseline to post-treatment visit is calculated by subtracting the Baseline measurement from the post-treatment measurement. | At Baseline, Week 4, 8, 12 and 16. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle Cell Disease, SCD, 6R-BH4, BH4, sapropterin dihydrochloride, endothelial dysfunction, Nitric Oxide, NO