Study of Kuvan Treatment in Adults With GTPCH Deficiency

Study Overview
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Brief Summary
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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.

Official Title
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Pilot Study to Assess Impact of Kuvan® Supplementation as an Adjunct Treatment in Subjects With Dominantly-inherited GTPCH Deficiency on Mood, Behavioral and Motor Phenotypes

Conditions
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GTP Cyclohydrolase Deficiency

Intervention / Treatment
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* Drug: Sapropterin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kuvan Cohort 1<br>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. This cohort will begin at a dose of 20mg/kg/day. | Drug: Sapropterin<br>* 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.<br>* Other names: Kuvan;|
| Experimental: Kuvan Cohort 2<br>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, but will plan on starting at 30 mg/kg/day. | Drug: Sapropterin<br>* 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.<br>* Other names: Kuvan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 8 wks, 12 wks | 
| Change in Neurotransmitter Metabolite Levels in Cerebral Spinal Fluid |  | Baseline, 8 wks, 12 wks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Anxiety Rating Scale | The Hamilton Anxiety Scale (HAS or HAMA) is a 14-item test measuring the severity of anxiety symptoms.Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. | Baseline, 8 wks, 12 wks, 24 wks (optional) | 
| Behavior Rating Inventory of Executive Function (BRIEF-A) Adult Version | The Behavior Rating Inventory of Executive Function-Adults (BRIEF-A) is a 75-item scale designed to assess self-reported behaviors associated with executive function. Answers are scored from 1, never a problem, to 7, always a problem. Higher scores indicate poor executive function. | Baseline, 8 wks, 12 wks, 24 wks (optional) | 
| Beck Depression Inventory | The Beck Depression Inventory (BDI) is a 21-item, self-rated scale that evaluates key symptoms of depression including mood, pessimism, sense of failure, self-dissatisfaction, guilt, punishment, self-dislike, self-accusation, suicidal ideas, crying, irritability, social withdrawal, indecisiveness, body image change, work difficulty, insomnia, fatigability, loss of appetite, weight loss, somatic preoccupation, and loss of libido. The 21 symptoms and attitudes contained in the BDI reflect the intensity of the depression; items receive a rating of zero to three to reflect their intensity and are summed linearly to create a score which ranges from 0 to 63. Scores from 0 through 9 indicate no or minimal depression; scores from 10 through 18 indicate mild to moderate depression; scores from 19 through 29 indicate moderate to severe depression; and scores from 30 through 63 indicate severe depression. | Baseline, 8 wks, 12 wks, 24 wks (optional) | 
| Brief Symptom Inventory | The Brief Symptom Inventory (BSI) consists of 53 items covering nine symptom dimensions: Somatization, Obsession-Compulsion, Interpersonal Sensitivity, Depression, Anxiety, Hostility, Phobic anxiety, Paranoid ideation and Psychoticism; and three global indices of distress: Global Severity Index, Positive Symptom Distress Index, and Positive Symptom Total. The global indices measure current or past level of symptomatology, intensity of symptoms, and number of reported symptoms, respectively. Each item of the BSI is rated on a 5-point scale of distress (0-4), ranging from not at all (0) at one pole to extremely (4) at the other. | Baseline, 8 wks, 12 wks, 24 wks (optional) | 
| Pittsburgh Sleep Quality Index | The Pittsburgh Sleep Quality Index (PSQI) The 19 self-rated items are combined to form seven component scores, each of which has a range of 0-3 points. In all cases, a score of 0 indicates no difficulty, while a score of 3 indicates severe difficulty. The component scores are then added to yield one global score, with a range of 0-21 points, 0 indicating no difficulty and 21 indicating severe difficulties in all areas | Baseline, 8 wks, 12 wks, 24 wks (optional) |