- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00445978
A Phase 2 Study of the Effects of 6R-BH4 in Subjects With Sickle Cell Disease
February 3, 2021 updated by: BioMarin Pharmaceutical
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
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.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Interventional
Enrollment (Actual)
32
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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District of Columbia
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Washington, District of Columbia, United States, 20060
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Georgia
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Augusta, Georgia, United States, 30912
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Savannah, Georgia, United States, 31404
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Indiana
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Indianapolis, Indiana, United States, 46260
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Michigan
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Detroit, Michigan, United States, 48201
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Flint, Michigan, United States, 48503
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New Jersey
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Hackensack, New Jersey, United States, 07601
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North Carolina
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Chapel Hill, North Carolina, United States, 27599
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19134
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Texas
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Galveston, Texas, United States, 77555
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Virginia
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Norfolk, Virginia, United States, 23507
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Richmond, Virginia, United States, 23298
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
15 years and older (Child, Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Sapropterin dihydrochloride
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.
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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.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
Time Frame: Up to 16 weeks
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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.
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Up to 16 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores
Time Frame: At Baseline, Week 4, 8, 12 and 16.
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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.
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At Baseline, Week 4, 8, 12 and 16.
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Change From Baseline in the Urine 8-Isoprostane
Time Frame: At Baseline, Week 4, 8, 12 and 16.
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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.
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At Baseline, Week 4, 8, 12 and 16.
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Change From Baseline in the Urine Spot Albumin to Creatinine Ratio
Time Frame: At Baseline, Week 4, 8, 12 and 16.
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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.
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At Baseline, Week 4, 8, 12 and 16.
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Change From Baseline in the Tricuspid Regurgitant Velocity (TRV)
Time Frame: At Baseline, Week 4, 8, 12 and 16.
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Change in tricuspid regurgitant velocity (TRV) from Baseline to post-treatment visit is calculated by subtracting the Baseline measurement from the post-treatment measurement.
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At Baseline, Week 4, 8, 12 and 16.
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Study Director: Saba Sile, MD, BioMarin Pharmaceutical
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
May 1, 2007
Primary Completion (Actual)
August 1, 2008
Study Completion (Actual)
June 1, 2009
Study Registration Dates
First Submitted
March 7, 2007
First Submitted That Met QC Criteria
March 7, 2007
First Posted (Estimate)
March 9, 2007
Study Record Updates
Last Update Posted (Actual)
February 25, 2021
Last Update Submitted That Met QC Criteria
February 3, 2021
Last Verified
February 1, 2021
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Hematologic Diseases
- Genetic Diseases, Inborn
- Anemia
- Anemia, Hemolytic, Congenital
- Anemia, Hemolytic
- Hemoglobinopathies
- Anemia, Sickle Cell
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Vasodilator Agents
- Membrane Transport Modulators
- Calcium-Regulating Hormones and Agents
- Calcium Channel Blockers
- Verapamil
Other Study ID Numbers
- SCD-001
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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