Sickle Cell DiseasePhase 2NCT00445978

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

A Phase 2 study testing Sapropterin Dihydrochloride in people with Sickle Cell Disease, run by BioMarin Pharmaceutical at 12 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 15 years and older
Conditions the study is for: Sickle Cell Disease
What is being tested?: Sapropterin Dihydrochloride
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 32 participants
Where: 12 sitesUnited States
Study dates: May 2007to Jun 2009
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 15 years and older
All sexes
No healthy volunteers
Child, Adult, Older adult

Who may be able to join

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.

Who cannot join

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.

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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.

Trial locations and contacts

12 sites in 1 country.

City, postcode or hospital

12 sites in 1 country

United States12 sites

Study site
Augusta, Georgia, 30912
Study site
Chapel Hill, North Carolina, 27599
Study site
Detroit, Michigan, 48201
Study site
Flint, Michigan, 48503
Study site
Galveston, Texas, 77555
Study site
Hackensack, New Jersey, 07601
Study site
Indianapolis, Indiana, 46260
Study site
Norfolk, Virginia, 23507
Study site
Philadelphia, Pennsylvania, 19134
Study site
Richmond, Virginia, 23298
Study site
Savannah, Georgia, 31404
Study site
Washington D.C., District of Columbia, 20060

Other trials in United States

About this study

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

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.

Read the 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.

Conditions: Sickle Cell Disease
Being tested: Sapropterin Dihydrochloride
Keywords: Sickle Cell Disease, SCD, 6R-BH4, BH4, sapropterin dihydrochloride, endothelial dysfunction, Nitric Oxide, NO
Medical subject headings: Anemia, Sickle Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Sapropterin DihydrochlorideDrug
Also called 6R-BH4
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.

Study groups in NCT00445978
Study group	Role	What they receive
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. Receives: Drug: Sapropterin Dihydrochloride

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: Up to 16 weeks

Secondary outcomes (4)

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

May 2007Jun 2009

First posted9 Mar 2007 (estimated)
Study startMay 2007
Primary completionAug 2008
Study completionJun 2009

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
More trials run by BioMarin PharmaceuticalThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Enrolment: 32 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00445978
Sponsor's protocol ID: SCD-001
Status last verified: Feb 2021
First submitted: 7 Mar 2007
Last updated: 25 Feb 2021
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

Active, not recruitingPhase 1/2
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat
Sickle Cell Disease, Hemolytic Anemia
RecruitingObservational study
HPC Offered for PRESERVE Expansion
Bone Marrow Transplant (BMT)
RecruitingPhase 1
Study to Evaluate the Safety and Tolerability of Escalating Doses of Fostamatinib in Subjects With Stable Sickle Cell Disease
Sickle Cell Disorders, Sickle Cell Disease
RecruitingPhase 4
Clinical and Biomarker Effects of Depot Medroxyprogesterone Acetate in Females With Sickle Cell Disease
Sickle Cell Disease (SCD), Vaso-Occlusive Pain Episode in Sickle Cell Disease
Not yet recruitingPhase 1
Buprenorphine for the Management of Pain in Children With Sickle Cell Disease
Sickle Cell Disease (SCD), Sickle Cell Disease Vaso-occlusive Crisis

All Sickle Cell Disease trials

Study at a glance

From the registry record, last updated by the sponsor on 25 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT00445978
Acronym / sponsor ID: SCD-001
Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease, SCD, 6R-BH4, BH4, sapropterin dihydrochloride, endothelial dysfunction, Nitric Oxide, NO
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 32 participants (actual)
Lead sponsor: BioMarin PharmaceuticalIndustry (pharma, biotech, devices)
Study start: May 2007 (actual)
Primary completion: Aug 2008 (actual)
Study completion: Jun 2009 (actual)
First posted: 9 Mar 2007 (estimated)
Results: Posted 28 Jan 2021

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
Sapropterin dihydrochloride	Experimental	Drug: Sapropterin Dihydrochloride2.5, 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.

Who may qualify

Ages: 15 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult, Older adult

Key inclusion criteria (7 listed)

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.

Key exclusion criteria (18 listed)

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]).

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Sapropterin DihydrochlorideAlso: 6R-BH4Subjects 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.	Drug	Sapropterin dihydrochloride

Primary outcome

Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
Time frame: Up to 16 weeks
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.

4 secondary outcomes

Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores
Time frame: At Baseline, Week 4, 8, 12 and 16.
Change From Baseline in the Urine 8-Isoprostane
Time frame: At Baseline, Week 4, 8, 12 and 16.
Change From Baseline in the Urine Spot Albumin to Creatinine Ratio
Time frame: At Baseline, Week 4, 8, 12 and 16.
Change From Baseline in the Tricuspid Regurgitant Velocity (TRV)
Time frame: At Baseline, Week 4, 8, 12 and 16.

Results and safety

Results posted to the registry on 28 Jan 2021, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Sapropterin Dihydrochloride	32	29

Primary outcome: Number of Subjects With Treatment Emergent Adverse Events (TEAEs)

Time frame: Up to 16 weeks. Count of participants. Unit: Participants

Measure	Sapropterin Dihydrochloride 2.5 mg/kg/Day n = 32	Sapropterin Dihydrochloride 5.0 mg/kg/Day n = 29	Sapropterin Dihydrochloride 10.0 mg/kg/Day n = 25	Sapropterin Dihydrochloride 20.0 mg/kg/Day n = 21
Subjects with any adverse event	27	18	20	15
Subjects with any serious adverse events	3	2	6	3
Subjects with any treatment-related adverse event	9	4	6	3
Any subject with a treatment-related serious adverse event	0	1	2	0
Any subject with an AE causing study discontinuation	1	1	0	1
Any subject with an SAE causing study discontinuation	1	1	0	0
Death	0	0	0	0

Population analysed: All Treated Subjects

4 secondary outcomes are reported in the full results.

Adverse events

Time frame: Up to 16 weeks. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Sapropterin Dihydrochloride 2.5 mg/kg/Day	3 of 32 (9.4%)	27 of 32 (84.4%)	0 of 32
Sapropterin Dihydrochloride 5.0 mg/kg/Day	2 of 29 (6.9%)	18 of 29 (62.1%)	0 of 29
Sapropterin Dihydrochloride 10.0 mg/kg/Day	6 of 25 (24%)	20 of 25 (80%)	0 of 25
Sapropterin Dihydrochloride 20.0 mg/kg/Day	3 of 21 (14.3%)	15 of 21 (71.4%)	0 of 21

Limitations and caveats (from the sponsor): 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.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
BioMarin Pharmaceutical Inc. websiteLink provided by the sponsor.

Related trials for Sickle Cell Disease

Active, not recruitingPhase 1/2
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat
Sickle Cell Disease, Hemolytic Anemia
RecruitingObservational study
HPC Offered for PRESERVE Expansion
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RecruitingPhase 1
Study to Evaluate the Safety and Tolerability of Escalating Doses of Fostamatinib in Subjects With Stable Sickle Cell Disease
Sickle Cell Disorders, Sickle Cell Disease
RecruitingPhase 4
Clinical and Biomarker Effects of Depot Medroxyprogesterone Acetate in Females With Sickle Cell Disease
Sickle Cell Disease (SCD), Vaso-Occlusive Pain Episode in Sickle Cell Disease
Not yet recruitingPhase 1
Buprenorphine for the Management of Pain in Children With Sickle Cell Disease
Sickle Cell Disease (SCD), Sickle Cell Disease Vaso-occlusive Crisis

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Saba Sile, MD study director

BioMarin Pharmaceutical

12 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Sapropterin Dihydrochloride in people with Sickle Cell Disease, run by BioMarin Pharmaceutical at 12 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 12 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Jan 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Subjects With Treatment Emergent Adverse Events (TEAEs) (time frame: Up to 16 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00445978.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2021.