Sickle Cell Disease
Conditions
Keywords
Sickle Cell Disease, SCD, 6R-BH4, BH4, sapropterin dihydrochloride, endothelial dysfunction, Nitric Oxide, NO
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.
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.
Interventions
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.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores | At Baseline, Week 4, 8, 12 and 16. | 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. |
| Change From Baseline in the Urine 8-Isoprostane | At Baseline, Week 4, 8, 12 and 16. | 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. |
| Change From Baseline in the Urine Spot Albumin to Creatinine Ratio | At Baseline, Week 4, 8, 12 and 16. | 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. |
| Change From Baseline in the Tricuspid Regurgitant Velocity (TRV) | At Baseline, Week 4, 8, 12 and 16. | Change in tricuspid regurgitant velocity (TRV) from Baseline to post-treatment visit is calculated by subtracting the Baseline measurement from the post-treatment measurement. |
Countries
United States
Participant flow
Recruitment details
This was a multicenter dose escalation study with 12 sites in the US in subjects with sickle cell disease (SCD). Only subjects with HbSS (homozygous SCD) and HbSC (heterozygous SCD) genotypes and at least 15 years of age were enrolled.
Pre-assignment details
Dose escalation was to take place at Week 4, 8, and 12; however some subjects initially maintained the previous dose and received escalated doses at a later time point during the dose interval. This delay was to adhere to the study protocol for escalation (for example, if a subject missed the appointment for PAT testing, dose escalation was delayed until testing could be performed), not due to safety concerns. Subjects not escalated in dose either maintained or reduced dose.
Participants by arm
| Arm | Count |
|---|---|
| Sapropterin Dihydrochloride Sapropterin dihydrochloride: Subjects will receive oral tablets, once-daily (for 2.5, 5, 10mg/kg/day doses) or twice-daily (for the 20 mg/kg/day dose) of 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. | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Week 0 - Week 4 (2.5 mg/kg/Day) | Adverse Event | 1 |
| Week 0 - Week 4 (2.5 mg/kg/Day) | Physician Decision | 1 |
| Week 0 - Week 4 (2.5 mg/kg/Day) | Study Compliance | 1 |
| Week 12 - Week 16 (20 mg/kg/Day) | Lost to Follow-up | 1 |
| Week 4 - Week 8 (5 mg/kg/Day) | Adverse Event | 1 |
| Week 4 - Week 8 (5 mg/kg/Day) | Lost to Follow-up | 1 |
| Week 4 - Week 8 (5 mg/kg/Day) | Physician Decision | 1 |
| Week 4 - Week 8 (5 mg/kg/Day) | Withdrew Consent | 1 |
| Week 8 - Week 12 (10 mg/kg/Day) | Pregnancy | 1 |
Baseline characteristics
| Characteristic | Sapropterin Dihydrochloride |
|---|---|
| Age, Continuous | 28.5 years STANDARD_DEVIATION 12 |
| PAT (peripheral arterial tonometry) at baseline (Ratio) Abnormal (PAT</= 1.67) | 18 Participants |
| PAT (peripheral arterial tonometry) at baseline (Ratio) Missing | 5 Participants |
| PAT (peripheral arterial tonometry) at baseline (Ratio) Normal (PAT > 1.67) | 9 Participants |
| Race/Ethnicity, Customized Black or African American | 32 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 32 Participants |
| SCD Genotype SC (heterozygous, 1 hemoglobin S allele, 1 hemoglobin C allele) | 13 participants |
| SCD Genotype SS (homozygous, 2 hemoglobin S alleles) | 19 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 13 Participants |
| TRV (tricuspid regurgitant velocity) at baseline (m/sec) TRV< 2.5 | 18 Participants |
| TRV (tricuspid regurgitant velocity) at baseline (m/sec) TRV>/= 2.5 | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 29 | 0 / 25 | 0 / 21 |
| other Total, other adverse events | 27 / 32 | 18 / 29 | 20 / 25 | 15 / 21 |
| serious Total, serious adverse events | 3 / 32 | 2 / 29 | 6 / 25 | 3 / 21 |
Outcome results
Primary
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.
Time frame: Up to 16 weeks
Population: All Treated Subjects
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any adverse event | 27 Participants |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with an SAE causing study discontinuation | 1 Participants |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with an AE causing study discontinuation | 1 Participants |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any serious adverse events | 3 Participants |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any treatment-related adverse event | 9 Participants |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with a treatment-related serious adverse event | 0 Participants |
| Sapropterin Dihydrochloride 5.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with an SAE causing study discontinuation | 1 Participants |
| Sapropterin Dihydrochloride 5.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with a treatment-related serious adverse event | 1 Participants |
| Sapropterin Dihydrochloride 5.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any treatment-related adverse event | 4 Participants |
| Sapropterin Dihydrochloride 5.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with an AE causing study discontinuation | 1 Participants |
| Sapropterin Dihydrochloride 5.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Sapropterin Dihydrochloride 5.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any serious adverse events | 2 Participants |
| Sapropterin Dihydrochloride 5.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any adverse event | 18 Participants |
| Sapropterin Dihydrochloride 10.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with a treatment-related serious adverse event | 2 Participants |
| Sapropterin Dihydrochloride 10.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any adverse event | 20 Participants |
| Sapropterin Dihydrochloride 10.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any serious adverse events | 6 Participants |
| Sapropterin Dihydrochloride 10.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any treatment-related adverse event | 6 Participants |
| Sapropterin Dihydrochloride 10.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with an AE causing study discontinuation | 0 Participants |
| Sapropterin Dihydrochloride 10.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with an SAE causing study discontinuation | 0 Participants |
| Sapropterin Dihydrochloride 10.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Sapropterin Dihydrochloride 20.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any treatment-related adverse event | 3 Participants |
| Sapropterin Dihydrochloride 20.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Sapropterin Dihydrochloride 20.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with an SAE causing study discontinuation | 0 Participants |
| Sapropterin Dihydrochloride 20.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any serious adverse events | 3 Participants |
| Sapropterin Dihydrochloride 20.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Subjects with any adverse event | 15 Participants |
| Sapropterin Dihydrochloride 20.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with an AE causing study discontinuation | 1 Participants |
| Sapropterin Dihydrochloride 20.0 mg/kg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Any subject with a treatment-related serious adverse event | 0 Participants |
Secondary
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.
Time frame: At Baseline, Week 4, 8, 12 and 16.
Population: At each timepoint of the dose-escalation phase, subjects with evaluable PAT score at the corresponding timepoint and baseline were included in the change from baseline analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores | Baseline | 1.5815 Ratio | Standard Deviation 0.4292 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores | Change from Baseline to Week 4 | 0.1317 Ratio | Standard Deviation 0.4811 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores | Change from Baseline to Week 8 | 0.2852 Ratio | Standard Deviation 0.602 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores | Change from Baseline to Week 12 | 0.3656 Ratio | Standard Deviation 0.5004 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores | Change from Baseline to Week 16 | 0.3604 Ratio | Standard Deviation 0.88 |
Secondary
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.
Time frame: At Baseline, Week 4, 8, 12 and 16.
Population: At each timepoint of the dose-escalation phase, subjects with tricuspid regurgitant velocity at the corresponding timepoint and baseline were included in the change from baseline analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Tricuspid Regurgitant Velocity (TRV) | Baseline | 2.09 m/sec | Standard Deviation 0.84 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Tricuspid Regurgitant Velocity (TRV) | Change from Baseline to Week 4 | 0.09 m/sec | Standard Deviation 0.53 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Tricuspid Regurgitant Velocity (TRV) | Change from Baseline to Week 8 | 0.03 m/sec | Standard Deviation 0.73 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Tricuspid Regurgitant Velocity (TRV) | Change from Baseline to Week 12 | 0.01 m/sec | Standard Deviation 0.43 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Tricuspid Regurgitant Velocity (TRV) | Change from Baseline to Week 16 | 0.16 m/sec | Standard Deviation 0.72 |
Secondary
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.
Time frame: At Baseline, Week 4, 8, 12 and 16.
Population: At each timepoint of the dose-escalation phase, subjects with urine 8-isoprostane at the corresponding timepoint and baseline were included in the change from baseline analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine 8-Isoprostane | Baseline | 1019.68 pg/mg creatinine | Standard Deviation 479.9 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine 8-Isoprostane | Change from Baseline to Week 4 | -27.58 pg/mg creatinine | Standard Deviation 622.53 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine 8-Isoprostane | Change from Baseline to Week 8 | -69.75 pg/mg creatinine | Standard Deviation 402.83 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine 8-Isoprostane | Change from Baseline to Week 12 | 24.71 pg/mg creatinine | Standard Deviation 355.71 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine 8-Isoprostane | Change from Baseline to Week 16 | -275.19 pg/mg creatinine | Standard Deviation 566.99 |
Secondary
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.
Time frame: At Baseline, Week 4, 8, 12 and 16.
Population: At each timepoint of the dose-escalation phase, subjects with urinary spot albumin to creatinine at the corresponding timepoint and baseline were included in the change from baseline analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine Spot Albumin to Creatinine Ratio | Baseline | 17.88 mg/mmol | Standard Deviation 42.44 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine Spot Albumin to Creatinine Ratio | Change from Baseline to Week 4 | 1.66 mg/mmol | Standard Deviation 27.43 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine Spot Albumin to Creatinine Ratio | Change from Baseline to Week 8 | -5.51 mg/mmol | Standard Deviation 25.31 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine Spot Albumin to Creatinine Ratio | Change from Baseline to Week 12 | -10.76 mg/mmol | Standard Deviation 24.73 |
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Change From Baseline in the Urine Spot Albumin to Creatinine Ratio | Change from Baseline to Week 16 | -9.32 mg/mmol | Standard Deviation 23.82 |