GTP Cyclohydrolase Deficiency
Conditions
Brief summary
The purpose of this study is to identify the dose of Kuvan needed to normalize the levels of tetrahydrobiopterin (BH4) in patients with a Guanosine Triphosphate Cyclohydrolase (GTPCH) deficiency and to asses the potential impact of oral Kuvan on mood and function in individuals with GTPCH deficiency who may be experiencing symptoms of anxiety, depression, fatigue, trouble concentrating, or memory loss. This will be a phase one study. The investigators will monitor patients over a period of three to six months while on the medication. Medication levels will be monitored by measuring the BH4 levels in cerebral spinal fluid (CSF). Patients will undergo a baseline lumbar puncture and two follow-up lumbar punctures for this purpose. The investigators will also monitor emotional function and motor function.
Interventions
DRUGSapropterin
Sapropterin will be taken daily for 12 or 24 weeks. Starting dose will be 20mg/kg/day and will increase at the 8 week visit to 30 mg/kg/day. Dosing may be further increased to as high as 40 mg/kg/day in attempt to normalize BH4 levels in CSF. Starting dose for Cohort 2 will be determined from data analysis in Cohort 1.
Sponsors
BioMarin Pharmaceutical
University of Utah
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* established diagnosis of GTPCH deficiency, supported by appropriate family history, CSF neurotransmitter studies, skin fibroblast enzyme assay and/or mutation analysis * minimum age 18 years * identified by self or others to have symptoms of anxiety, depression, fatigue, or other neurocognitive dysfunction (trouble concentrating, memory loss, etc) * willingness to undergo at least 2 CSF evaluations for BH4 and neurotransmitter levels over an 8 to 12 week period
Exclusion criteria
* age \< 18 years old * unwillingness to undergo repeated CSF analysis * lack of supporting diagnostic criteria * concomitant medical problems or medications which would increase risk of Kuvan® * concomitant psychiatric state, such as severe depression with suicidal ideation that requires immediate referral and alternative treatment intervention * prior history of back surgery, abnormality or chronic pain that in the opinion of the investigator would increase risks associated with lumbar puncture * significant obesity that might increase difficulty or risk in performing lumbar puncture * if female, unwillingness to use birth control during the period of study drug administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in BH4 Levels in Cerebral Spinal Fluid | Baseline, 8 wks, 12 wks | Identify dosing range of oral Kuvan® necessary and sufficient to normalize CSF BH4 levels in adults with GTPCH Deficiency. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from August 2011 through August 2013. Participants were patients who had been seen clinically for GTPCH deficiency and indicated previously that they would be interested in future research.
Pre-assignment details
This is a pilot study and all participants are in the treatment group.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 This cohort will be enrolled first. Analysis will be done to determine the optimum dosing of Kuvan to normalize BH4 levels in the Cerebral Spinal Fluid.
Sapropterin: Sapropterin will be taken daily for 12 or 24 weeks. Starting dose will be 20mg/kg/day and will increase at the 8 week visit to 30 mg/kg/day. Dosing may be further increased to as high as 40 mg/kg/day in attempt to normalize BH4 levels in CSF. Starting dose for Cohort 2 will be determined from data analysis in Cohort 1. | 6 |
| Cohort 2 Participants in cohort 2 will be enrolled after the analysis of cohort 1 data has taken place. Dosing for cohort 2 will be based on results obtained in cohort 1.
Sapropterin: Sapropterin will be taken daily for 12 or 24 weeks. Starting dose will be 20mg/kg/day and will increase at the 8 week visit to 30 mg/kg/day. Dosing may be further increased to as high as 40 mg/kg/day in attempt to normalize BH4 levels in CSF. Starting dose for Cohort 2 will be determined from data analysis in Cohort 1. | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Cohort 1 | Cohort 2 |
|---|---|---|---|
| Age, Continuous | 35 years | 42 years | 28 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 6 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 6 Participants | 6 Participants |
| Region of Enrollment United States | 12 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 | 0 / 6 |
Outcome results
Primary
Change in BH4 Levels in Cerebral Spinal Fluid
Identify dosing range of oral Kuvan® necessary and sufficient to normalize CSF BH4 levels in adults with GTPCH Deficiency.
Time frame: Baseline, 8 wks, 12 wks
Population: Data from 4 of 6 participants was analyzed for Kuvan Cohort 1 and for Kuvan Cohort 2 for this outcome measure. 2 participant withdrew, 1 participant's diagnosis was reclassified and we were unable to obtain baseline CSF on 1 participant.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change in BH4 Levels in Cerebral Spinal Fluid | Change in BH4 from Baseline at 8 weeks | 6 nmol/L | Standard Deviation 1.4 |
| Cohort 1 | Change in BH4 Levels in Cerebral Spinal Fluid | Change in BH4 from Baseline at 12 weeks | 5.3 nmol/L | Standard Deviation 3.8 |
| Cohort 2 | Change in BH4 Levels in Cerebral Spinal Fluid | Change in BH4 from Baseline at 8 weeks | 10.7 nmol/L | Standard Deviation 4.8 |
| Cohort 2 | Change in BH4 Levels in Cerebral Spinal Fluid | Change in BH4 from Baseline at 12 weeks | 13.2 nmol/L | Standard Deviation 3.9 |