A Phase 2 Study of the Effects of 6R-BH4 in Subjects With Sickle Cell Disease
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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. |
Drug: Sapropterin Dihydrochloride
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:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Washington | District of Columbia | United States | 20060 | |
| 2 | Augusta | Georgia | United States | 30912 | |
| 3 | Savannah | Georgia | United States | 31404 | |
| 4 | Indianapolis | Indiana | United States | 46260 | |
| 5 | Detroit | Michigan | United States | 48201 | |
| 6 | Flint | Michigan | United States | 48503 | |
| 7 | Hackensack | New Jersey | United States | 07601 | |
| 8 | Chapel Hill | North Carolina | United States | 27599 | |
| 9 | Philadelphia | Pennsylvania | United States | 19134 | |
| 10 | Galveston | Texas | United States | 77555 | |
| 11 | Norfolk | Virginia | United States | 23507 | |
| 12 | Richmond | Virginia | United States | 23298 |
Sponsors and Collaborators
- BioMarin Pharmaceutical
Investigators
- Study Director: Saba Sile, MD, BioMarin Pharmaceutical
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- SCD-001
Study Results
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 Detail | 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. |
| Arm/Group Title | Sapropterin Dihydrochloride |
|---|---|
| Arm/Group Description | 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. Prior to dose escalation, the investigator evaluated each subject's safety profile at the previous dose level to determine if the subject would escalate to the next dose level; maintain the same dose; or de-escalate to the previous dose. |
| Period Title: Week 0 - Week 4 (2.5 mg/kg/Day) | |
| STARTED | 32 |
| COMPLETED | 29 |
| NOT COMPLETED | 3 |
| Period Title: Week 0 - Week 4 (2.5 mg/kg/Day) | |
| STARTED | 29 |
| Received Escalated Dose | 29 |
| COMPLETED | 25 |
| NOT COMPLETED | 4 |
| Period Title: Week 0 - Week 4 (2.5 mg/kg/Day) | |
| STARTED | 25 |
| Received Escalated Dose | 25 |
| COMPLETED | 24 |
| NOT COMPLETED | 1 |
| Period Title: Week 0 - Week 4 (2.5 mg/kg/Day) | |
| STARTED | 24 |
| Received Escalated Dose | 21 |
| COMPLETED | 23 |
| NOT COMPLETED | 1 |
Baseline Characteristics
| Arm/Group Title | Sapropterin Dihydrochloride |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 32 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
28.5
(12.0)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
19
59.4%
|
| Male |
13
40.6%
|
| Race/Ethnicity, Customized (Count of Participants) | |
| Black or African American |
32
100%
|
| Race/Ethnicity, Customized (Count of Participants) | |
| Not Hispanic or Latino |
32
100%
|
| SCD Genotype (participants) [Number] | |
| SS (homozygous, 2 hemoglobin S alleles) |
19
59.4%
|
| SC (heterozygous, 1 hemoglobin S allele, 1 hemoglobin C allele) |
13
40.6%
|
| PAT (peripheral arterial tonometry) at baseline (Ratio) (Count of Participants) | |
| Normal (PAT > 1.67) |
9
28.1%
|
| Abnormal (PAT</= 1.67) |
18
56.3%
|
| Missing |
5
15.6%
|
| TRV (tricuspid regurgitant velocity) at baseline (m/sec) (Count of Participants) | |
| TRV< 2.5 |
18
56.3%
|
| TRV>/= 2.5 |
14
43.8%
|
Outcome Measures
| Title | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Treated Subjects |
| Arm/Group Title | Sapropterin Dihydrochloride 2.5 mg/kg/Day | Sapropterin Dihydrochloride 5.0 mg/kg/Day | Sapropterin Dihydrochloride 10.0 mg/kg/Day | Sapropterin Dihydrochloride 20.0 mg/kg/Day |
|---|---|---|---|---|
| Arm/Group Description | Sapropterin dihydrochloride 2.5 mg/kg/day at Incidence | Sapropterin dihydrochloride 5.0 mg/kg/day at Incidence | Sapropterin dihydrochloride 10.0 mg/kg/day at Incidence | Sapropterin dihydrochloride 20.0 mg/kg/day at Incidence |
| Measure Participants | 32 | 29 | 25 | 21 |
| Subjects with any adverse event |
27
84.4%
|
18
NaN
|
20
NaN
|
15
NaN
|
| Subjects with any serious adverse events |
3
9.4%
|
2
NaN
|
6
NaN
|
3
NaN
|
| Subjects with any treatment-related adverse event |
9
28.1%
|
4
NaN
|
6
NaN
|
3
NaN
|
| Any subject with a treatment-related serious adverse event |
0
0%
|
1
NaN
|
2
NaN
|
0
NaN
|
| Any subject with an AE causing study discontinuation |
1
3.1%
|
1
NaN
|
0
NaN
|
1
NaN
|
| Any subject with an SAE causing study discontinuation |
1
3.1%
|
1
NaN
|
0
NaN
|
0
NaN
|
| Death |
0
0%
|
0
NaN
|
0
NaN
|
0
NaN
|
| Title | Change From Baseline in the Peripheral Arterial Tonometry (PAT) Scores |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Sapropterin Dihydrochloride |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 27 |
| Baseline |
1.5815
(0.4292)
|
| Change from Baseline to Week 4 |
0.1317
(0.4811)
|
| Change from Baseline to Week 8 |
0.2852
(0.6020)
|
| Change from Baseline to Week 12 |
0.3656
(0.5004)
|
| Change from Baseline to Week 16 |
0.3604
(0.8800)
|
| Title | Change From Baseline in the Urine 8-Isoprostane |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Sapropterin Dihydrochloride |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 32 |
| Baseline |
1019.68
(479.90)
|
| Change from Baseline to Week 4 |
-27.58
(622.53)
|
| Change from Baseline to Week 8 |
-69.75
(402.83)
|
| Change from Baseline to Week 12 |
24.71
(355.71)
|
| Change from Baseline to Week 16 |
-275.19
(566.99)
|
| Title | Change From Baseline in the Urine Spot Albumin to Creatinine Ratio |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Sapropterin Dihydrochloride |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 26 |
| Baseline |
17.88
(42.44)
|
| Change from Baseline to Week 4 |
1.66
(27.43)
|
| Change from Baseline to Week 8 |
-5.51
(25.31)
|
| Change from Baseline to Week 12 |
-10.76
(24.73)
|
| Change from Baseline to Week 16 |
-9.32
(23.82)
|
| Title | Change From Baseline in the Tricuspid Regurgitant Velocity (TRV) |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Sapropterin Dihydrochloride |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 32 |
| Baseline |
2.09
(0.84)
|
| Change from Baseline to Week 4 |
0.09
(0.53)
|
| Change from Baseline to Week 8 |
0.03
(0.73)
|
| Change from Baseline to Week 12 |
0.01
(0.43)
|
| Change from Baseline to Week 16 |
0.16
(0.72)
|
Adverse Events
| Time Frame | Up to 16 weeks | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||
| Arm/Group Title | Sapropterin Dihydrochloride 2.5 mg/kg/Day | Sapropterin Dihydrochloride 5.0 mg/kg/Day | Sapropterin Dihydrochloride 10.0 mg/kg/Day | Sapropterin Dihydrochloride 20.0 mg/kg/Day | ||||
| Arm/Group Description | Sapropterin dihydrochloride 2.5 mg/kg/day at Incidence | Sapropterin dihydrochloride 5.0 mg/kg/day at Incidence | Sapropterin dihydrochloride 10.0 mg/kg/day at Incidence | Sapropterin dihydrochloride 20.0 mg/kg/day at Incidence | ||||
All Cause Mortality |
||||||||
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Sapropterin Dihydrochloride 5.0 mg/kg/Day | Sapropterin Dihydrochloride 10.0 mg/kg/Day | Sapropterin Dihydrochloride 20.0 mg/kg/Day | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
Serious Adverse Events |
||||||||
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Sapropterin Dihydrochloride 5.0 mg/kg/Day | Sapropterin Dihydrochloride 10.0 mg/kg/Day | Sapropterin Dihydrochloride 20.0 mg/kg/Day | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/32 (9.4%) | 2/29 (6.9%) | 6/25 (24%) | 3/21 (14.3%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Sickle cell anaemia with crisis | 3/32 (9.4%) | 2/29 (6.9%) | 5/25 (20%) | 3/21 (14.3%) | ||||
| Anaemia | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Leukocytosis | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Nervous system disorders | ||||||||
| Migraine | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Dyspnoea | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| Sapropterin Dihydrochloride 2.5 mg/kg/Day | Sapropterin Dihydrochloride 5.0 mg/kg/Day | Sapropterin Dihydrochloride 10.0 mg/kg/Day | Sapropterin Dihydrochloride 20.0 mg/kg/Day | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 27/32 (84.4%) | 18/29 (62.1%) | 20/25 (80%) | 15/21 (71.4%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Sickle cell anaemia with crisis | 9/32 (28.1%) | 7/29 (24.1%) | 10/25 (40%) | 4/21 (19%) | ||||
| Leukocytosis | 0/32 (0%) | 1/29 (3.4%) | 1/25 (4%) | 1/21 (4.8%) | ||||
| Anaemia | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 1/21 (4.8%) | ||||
| Cardiac disorders | ||||||||
| Bundle branch block right | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Tachycardia | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Endocrine disorders | ||||||||
| Goitre | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Eye disorders | ||||||||
| Ocular icterus | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Nausea | 2/32 (6.3%) | 0/29 (0%) | 2/25 (8%) | 1/21 (4.8%) | ||||
| Vomiting | 2/32 (6.3%) | 0/29 (0%) | 2/25 (8%) | 0/21 (0%) | ||||
| Constipation | 1/32 (3.1%) | 0/29 (0%) | 1/25 (4%) | 1/21 (4.8%) | ||||
| Abdominal distension | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Abdominal pain lower | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Dental caries | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Diarrhoea | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Flatulence | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Gastroenteritis viral | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Hiatus hernia | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Stomach discomfort | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| General disorders | ||||||||
| Pyrexia | 2/32 (6.3%) | 1/29 (3.4%) | 2/25 (8%) | 1/21 (4.8%) | ||||
| Non-cardiac chest pain | 2/32 (6.3%) | 0/29 (0%) | 2/25 (8%) | 0/21 (0%) | ||||
| Asthenia | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 1/21 (4.8%) | ||||
| Cyst | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Fatigue | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Flank pain | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Oedma | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Pain | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Tenderness | 0/32 (0%) | 1/29 (3.4%) | 1/25 (4%) | 0/21 (0%) | ||||
| Hepatobiliary disorders | ||||||||
| Hepatomegaly | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Immune system disorders | ||||||||
| Allergic Sinusitis | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Infections and infestations | ||||||||
| Urinary tract infection | 1/32 (3.1%) | 0/29 (0%) | 2/25 (8%) | 0/21 (0%) | ||||
| Gastroenteritis | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 1/21 (4.8%) | ||||
| Nasopharyngitis | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Upper respiratory tract infection | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 1/21 (4.8%) | ||||
| Bronchitis acute | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Hordeolum | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Infection | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Otitis media | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Otitis media acute | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Pharyngitis | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Pneumonia | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Sinusitis | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Skin papilloma | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Urinary tract infection fungal | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Injury | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Investigations | ||||||||
| Electrocardiogram T wave abnormal | 1/32 (3.1%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Alanine aminotransferase increased | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Albumin urine | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Albumin urine present | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Blood bicarbonate decreased | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Blood creatinine increased | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Blood pressure increased | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Blood uric acid increased | 1/32 (3.1%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Cardiac mumur | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Liver function test abnormal | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Mammogram abnormal | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Urinary sediment present | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Weight increased | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| White blood cells urine positive | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Anorexia | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Hyperkalaemia | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Hypervolaemia | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Hypoglycaemia | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Hypovolaemia | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Vitamin B12 deficiency | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Pain in extremity | 3/32 (9.4%) | 3/29 (10.3%) | 0/25 (0%) | 0/21 (0%) | ||||
| Back pain | 0/32 (0%) | 1/29 (3.4%) | 1/25 (4%) | 1/21 (4.8%) | ||||
| Arthralgia | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 2/21 (9.5%) | ||||
| Gout | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Joint sprain | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Joint Swelling | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Muscle spasms | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Musculoskeletal pain | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Sacral pain | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Nervous system disorders | ||||||||
| Headache | 4/32 (12.5%) | 1/29 (3.4%) | 2/25 (8%) | 0/21 (0%) | ||||
| Insomnia | 1/32 (3.1%) | 0/29 (0%) | 2/25 (8%) | 1/21 (4.8%) | ||||
| Migraine | 2/32 (6.3%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Paraesthesia | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Psychiatric disorders | ||||||||
| Anxiety | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Depression | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Reproductive system and breast disorders | ||||||||
| Vaginal Pain | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Menstrual disorder | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Pulmonary hypertension | 1/32 (3.1%) | 1/29 (3.4%) | 1/25 (4%) | 0/21 (0%) | ||||
| Dyspnoea | 0/32 (0%) | 0/29 (0%) | 2/25 (8%) | 1/21 (4.8%) | ||||
| Hypoxia | 1/32 (3.1%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Nasal congestion | 1/32 (3.1%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Sinusitis | 1/32 (3.1%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Bronchospasm | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Cough | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Nasal oedema | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Pharyngitis | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Upper respiratory tract congestion | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Dermatitis acneiform | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Dermatitis atopic | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Eczema | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Erythema | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Pigmentation disorder | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Pruritus | 0/32 (0%) | 0/29 (0%) | 0/25 (0%) | 1/21 (4.8%) | ||||
| Rash | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Rash macular | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Skin discolouration | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
| Skin lesion | 0/32 (0%) | 1/29 (3.4%) | 0/25 (0%) | 0/21 (0%) | ||||
| Vascular disorders | ||||||||
| Arterial thrombosis limb | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Ecchymosis | 0/32 (0%) | 0/29 (0%) | 1/25 (4%) | 0/21 (0%) | ||||
| Orthostatic hypotension | 1/32 (3.1%) | 0/29 (0%) | 0/25 (0%) | 0/21 (0%) | ||||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Joshua Lilienstein/Medical Director, Global Medical Affairs |
|---|---|
| Organization | BioMarin Pharmaceutical Inc. |
| Phone | 651.523.0310 |
| MEDINFO@bmrn.com |
- SCD-001