Phenylketonuria
Conditions
Keywords
PKU
Brief summary
The objective of this study is to evaluate the safety of long-term treatment with Phenoptin in subjects with phenylketonuria (PKU) who participated in Phase 3 clinical studies with Phenoptin.
Interventions
5-20mg/kg/day orally, dose may be adjusted up or down as needed at the discretion of the investigator in increments of 5mg/kg/day.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participation in study PKU-004 or PKU-006 * 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 parent or legal guardian, after the nature of the study has been explained, and prior to any research-related procedures * Negative urine pregnancy test at screening (females of child-bearing potential) * Willing and able to comply with all study procedures
Exclusion criteria
* Non-responsive to prior treatment with Phenoptin based on participation in PKU-004 or PKU-006 * Perceived to be unreliable or unavailable for study participation or, if under the age of 18 years, have parents or legal guardians who are perceived to be unreliable or unavailable * Terminated early from PKU-004 or PKU-006, except for subjects in PKU-004 that rolled into PKU-008 at Week 22, subjects in PKU-006 that rolled into PKU-008 at Week 10, or subjects in PKU-006 that terminated due to elevated Phe levels following dietary Phe increases * Use of any investigational product other than Phenoptin within 30 days prior to screening, or anticipated requirement for any investigational agent prior to completion of all scheduled study assessments * Positive urine pregnancy test at screening (non-sterile females of child-bearing potential only), already known to be pregnant or breastfeeding or planning a pregnancy in self or partner during the study * Female subjects of childbearing potential must be using an effective method of birth control, as determined by the PI, and willing to continue to use acceptable birth control measures * Concurrent disease or condition that would interfere with study participation or safety (e.g., seizure disorder, oral steroid-dependent asthma or other condition requiring oral or parenteral corticosteroid administration, or insulin-dependent diabetes) * Any condition that, in the view of the PI, renders the subject at high risk from treatment compliance and/or completing the study * ALT \> 2 times the upper limit of normal (i.e., Grade 1 or higher based on World Health Organization Toxicity Criteria) at screening (see Appendix 2) * Serious neuropsychiatric illness (e.g., major depression) not currently under medical control * Prior history of organ transplantation * Requirement for concomitant treatment with any drug known to inhibit folate synthesis (e.g., methotrexate) * Concurrent use of levodopa * Clinical diagnosis of primary BH4 deficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tabulation of the Incidence and Frequency of All AEs and SAEs That Occur Throughout the Study. | Baseline through Final Visit (a Maximum of 30 months) with AEs collected at month 3 and 6 then at 6 month intervals | Safety was assessed with regards to the rate and type of AEs, clinically significant changes to vital signs and/or physical examination findings, and clinically significant changes in laboratory test results. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Following Blood Phe Levels. | Baseline through Final Visit (a Maximum of 30 months) with blood phe samples taken at months 3 and 6 then at 6 month intervals | There were no pre-specified efficacy analysis, blood Phe samples were taken at each visit. Blood Phe concentrations remained within levels consistent with local clinical site recommendations for blood Phe control. |
Countries
United States
Participant flow
Recruitment details
Subjects had to have previously participated in study PKU-004 (NCT00225615) or PKU-006 (NCT00272792)
Pre-assignment details
The last assessment obtained in PKU-004 or PKU-006 could be used to determine eligibility for this study provided assessment was conducted fewer than six weeks prior to PKU-008 Day 1.
Participants by arm
| Arm | Count |
|---|---|
| Total Patient Population The mean (+/- SD) daily dose of study drug was 16.4 (+/-4.4) mg/kg. The final dose prescribed was 20 mg/kg/day for 73 (65.8%) subjects, 10 mg/kg/day for 33 (29.7%) subjects, and 5 mg/kg/day for 5 (4.5%) subjects. | 111 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Lack of Efficacy | 4 |
| Overall Study | Moved out of country | 2 |
| Overall Study | Uncooperative/Noncompliant | 3 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Total Patient Population |
|---|---|
| Age Continuous | 16.4 years STANDARD_DEVIATION 10.2 |
| Age, Customized >=12 to <18 | 28 participants |
| Age, Customized >=18 | 39 participants |
| Age, Customized >=4 to <8 | 20 participants |
| Age, Customized >=8 to <12 | 24 participants |
| Race/Ethnicity, Customized Asian/Asian Pacific Islander | 1 participants |
| Race/Ethnicity, Customized Caucasian | 108 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants |
| Region of Enrollment Europe | 57 participants |
| Region of Enrollment North America | 54 participants |
| Sex: Female, Male Female | 44 Participants |
| Sex: Female, Male Male | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 93 / 111 |
| serious Total, serious adverse events | 7 / 111 |
Outcome results
Primary
Tabulation of the Incidence and Frequency of All AEs and SAEs That Occur Throughout the Study.
Safety was assessed with regards to the rate and type of AEs, clinically significant changes to vital signs and/or physical examination findings, and clinically significant changes in laboratory test results.
Time frame: Baseline through Final Visit (a Maximum of 30 months) with AEs collected at month 3 and 6 then at 6 month intervals
Population: Percentage of total population who experienced an AE or SAE presented here. For full list of SAEs, and AEs experienced with a frequency of greater than 5%, see the Reported Adverse Event section.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Total Patient Population | Tabulation of the Incidence and Frequency of All AEs and SAEs That Occur Throughout the Study. | % of Subjects Reporting Any Adverse Event | 83.8 percentage of subjects reporting events |
| Total Patient Population | Tabulation of the Incidence and Frequency of All AEs and SAEs That Occur Throughout the Study. | % of Subjects Reporting Related Adverse Events | 33.3 percentage of subjects reporting events |
| Total Patient Population | Tabulation of the Incidence and Frequency of All AEs and SAEs That Occur Throughout the Study. | % of Subjects Reporting Serious Adverse Events | 6.3 percentage of subjects reporting events |
| Total Patient Population | Tabulation of the Incidence and Frequency of All AEs and SAEs That Occur Throughout the Study. | % of Subjects Reporting Related Serious AEs | 0.9 percentage of subjects reporting events |
Secondary
Following Blood Phe Levels.
There were no pre-specified efficacy analysis, blood Phe samples were taken at each visit. Blood Phe concentrations remained within levels consistent with local clinical site recommendations for blood Phe control.
Time frame: Baseline through Final Visit (a Maximum of 30 months) with blood phe samples taken at months 3 and 6 then at 6 month intervals
Population: The population includes all subjects who received at least one dose of study drug during the study and had at least one measurement of blood Phe level.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Total Patient Population | Following Blood Phe Levels. | Month 24 Change from Baseline (N=45) | -122.2 micromoles per liter | Standard Deviation 281.03 |
| Total Patient Population | Following Blood Phe Levels. | Baseline Blood Phe Level (N=111) | 607.4 micromoles per liter | Standard Deviation 328.44 |
| Total Patient Population | Following Blood Phe Levels. | Month 3 Blood Phe Level (N=109) | 504.6 micromoles per liter | Standard Deviation 316.33 |
| Total Patient Population | Following Blood Phe Levels. | Month 3 Change from Baseline (N=109) | -105.7 micromoles per liter | Standard Deviation 287.2 |
| Total Patient Population | Following Blood Phe Levels. | Month 6 Blood Phe Level (N=104) | 529.9 micromoles per liter | Standard Deviation 332.45 |
| Total Patient Population | Following Blood Phe Levels. | Month 6 Change from Baseline (N=104) | -68.0 micromoles per liter | Standard Deviation 310.76 |
| Total Patient Population | Following Blood Phe Levels. | Month 12 Blood Phe Level (N=97) | 494.4 micromoles per liter | Standard Deviation 330.57 |
| Total Patient Population | Following Blood Phe Levels. | Month 12 Change from Baseline (N=97) | -95.7 micromoles per liter | Standard Deviation 304.81 |
| Total Patient Population | Following Blood Phe Levels. | Month 18 Blood Phe Level (N=58) | 526.9 micromoles per liter | Standard Deviation 357.43 |
| Total Patient Population | Following Blood Phe Levels. | Month 18 Change from Baseline (N=58) | -92.8 micromoles per liter | Standard Deviation 306.02 |
| Total Patient Population | Following Blood Phe Levels. | Month 24 Blood Phe Level (N=45) | 482.0 micromoles per liter | Standard Deviation 322.55 |
| Total Patient Population | Following Blood Phe Levels. | Month 30 Blood Phe Level (N=1) | 808.0 micromoles per liter | — |
| Total Patient Population | Following Blood Phe Levels. | Month 30 Change from Baseline (N=1) | 542.0 micromoles per liter | — |