Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Phenylketonuria (PKU) Patients

Study Overview
=================
Brief Summary
-----------------
This double-blind, placebo-controlled, randomized study is designed to evaluate the safety and therapeutic effects of sapropterin dihydrochloride on neuropsychiatric symptoms in subjects with PKU.

Detailed Description
-----------------
Phenylketonuria (PKU) results from deficient phenylalanine hydroxylase (PAH) activity and leads to toxic phenylalanine (Phe) accumulation in patients with PKU causing mental retardation, microcephaly, delayed speech, seizures, psychiatric symptoms and behavioral abnormalities. Although for most PKU patients early initiation of dietary treatment prevents severe complications, discontinuation of dietary restrictions at an early age is associated with poor cognitive development and neuropsychiatric disorders are present even in early-treated and well controlled PKU patients. This study, PKU-016, will be conducted in PKU patients to evaluate the therapeutic effects of sapropterin dihydrochloride on the symptoms of attention deficit hyperactivity disorder (ADHD), depression, and anxiety.

Official Title
-----------------
A Double-blind, Placebo-controlled, Randomized Study to Evaluate the Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Subjects With Phenylketonuria

Conditions
-----------------
Phenylketonuria

Intervention / Treatment
-----------------
* Drug: Sapropterin dihydrochloride
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ≥ 8 years of age Confirmed diagnosis of PKU Willing to continue current diet (typical diet for the 3 months prior to study entry) unchanged while participating in the study Willing and able to provide written, signed informed consent or in the case of subjects under the age of 18, 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 Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study and for at least 30 days following the last dose of sapropterin dihydrochloride 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 in menopause at least 2 years, or had tubal ligation at least 1 year prior to screening, or have had total hysterectomy. Willing and able to comply with all study procedure Exclusion Criteria: Has known hypersensitivity to sapropterin dihydrochloride or its excipients Subject breastfeeding at screening or planning to become pregnant (subject or partner) at any time during the study Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to the completion of all scheduled study assessments Received sapropterin dihydrochloride within 16 weeks of randomization Have initiated or adjusted medication for treatment of ADHD, depression, or anxiety ≤ 8 weeks prior to randomization Taking medication known to inhibit folate synthesis (eg, methotrexate) Any condition requiring treatment with levodopa or any PDE-5 inhibitor Concurrent disease or condition that would interfere with study participation, compliance or safety as determined by the Investigator 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

Ages Eligible for Study
-----------------
Minimum Age: 8 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sapropterin dihydrochloride<br> | Drug: Sapropterin dihydrochloride<br>* A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact).<br>* Other names: 6R BH4;|
| Placebo Comparator: Tablet without active ingredient<br> | Drug: Placebo<br>* Placebo (tablet without active ingredient) is dosed once/day for the first 13 weeks of the study.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 13 | Effects of 6R-BH4 on symptoms of ADHD in PKU subjects who had symptoms of ADHD at screening in the subjects that had a blood Phe level reduction after treatment with 6R-BH4. The total ADHD-RS score and the corrected total ARS score range from 0 to 54, with higher scores corresponding to worse severity of ADHD symptoms. | Baseline to Week 13 | 
| Number of Participants With a Score of 1 or 2 in Global Function Evaluation (CGI-I) From Baseline to Week 13. | Effects of 6R-BH4 on global function in PKU subjects in subjects that had a blood Phe level reduction after treatment with 6R-BH4 at screening. The CGI-I is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. | 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 13 | Effects of 6R-BH4 on symptoms of anxiety in PKU subjects who had a blood Phe level reduction after treatment with 6R-BH4. HAM-A Score is a total score ranging from 0 to 56 with higher scores corresponding to worse severity of anxiety symptoms. The HAM-A has 14 items, each measuring specific anxiety symptom clusters. Each item is given a 5-point-score as: 0, absent; 1, mild; 2, moderate; 3, severe; or 4, incapacitating. | Baseline to Week 13 | 
| Change in Hamilton Depression Rating Scale (HAM-D) Score From Baseline to Week 13 | Effects of 6R-BH4 on symptoms of depression in PKU subjects who had a blood Phe level reduction after treatment with 6R-BH4. HAM-D Score is a total score ranging from 0 to 48 with higher scores corresponding to worse severity of depression. The HAM-D is a 17-item depression rating scale. Nine of the items are scored on a 5-point scale as: 0, absence of depressive symptom being measured; 1, doubt concerning the presence of the symptom; 2, mild symptoms; 3, moderate symptoms; or 4, severe symptoms. The remaining 8 items are scored on a 3-point scale as: 0, absence; 1, doubt on the presence of the symptom; or 2, clear presence of symptoms. | Baseline to Week 13 | 
| Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 13 | Effects of 6R-BH4 on global function in PKU subjects who had a blood Phe level reduction after treatment with 6R-BH4. CGI-S is a 7-point scale that requires the clinician to rate the severity of the subject's mental illness at the time of assessment, relative to clinician's past experience with subjects who have the same diagnosis. Considering total clinical experience, a subject is assessed on the severity of mental illness at the time of rating as: 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 6, severely ill; or 7, among the most extremely ill. | Baseline to Week 13 | 
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 13 | Effects of 6R-BH4 on executive function in PKU subjects who had a blood Phe level reduction after treatment with 6R-BH4. The scoring for the GEC T Score is complex and is achieved using proprietary software designed to generate scores based on raw data collected. Higher scores suggest a higher level of dysfunction. | Baseline to Week 13 | 
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 13 | Effects of 6R-BH4 on executive function in PKU subjects who had a blood Phe level reduction after treatment with 6R-BH4. The scoring for the GEC T Score is complex and is achieved using proprietary software designed to generate scores based on raw data collected. Higher scores suggest a higher level of dysfunction. | Baseline to Week 13 | 
| Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Week 13 to Week 26 | Durability of the therapeutic effect of 6R-BH4 on ADHD through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. The total ADHD-RS score and the corrected total ARS score range from 0 to 54, with higher scores corresponding to worse severity of ADHD symptoms. | Week 13 to Week 26 | 
| Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Week 13 to Week 26 | Durability of the therapeutic effect of 6R-BH4 on anxiety through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. HAM-A Score is a total score ranging from 0 to 56 with higher scores corresponding to worse severity of anxiety symptoms. The HAM-A has 14 items, each measuring specific anxiety symptom clusters. Each item is given a 5-point-score as: 0, absent; 1, mild; 2, moderate; 3, severe; or 4, incapacitating. | Week 13 to Week 26 | 
| Change in Hamilton Depression Rating Scale (HAM-D) Score From Week 13 to Week 26 | Durability of the therapeutic effect of 6R-BH4 on depression through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. HAM-D Score is a total score ranging from 0 to 48 with higher scores corresponding to worse severity of depression. The HAM-D is a 17-item depression rating scale. Nine of the items are scored on a 5-point scale as: 0, absence of depressive symptom being measured; 1, doubt concerning the presence of the symptom; 2, mild symptoms; 3, moderate symptoms; or 4, severe symptoms. The remaining 8 items are scored on a 3-point scale as: 0, absence; 1, doubt on the presence of the symptom; or 2, clear presence of symptoms. | Week 13 to Week 26 | 
| Change in Clinical Global Impression-Severity (CGI-S) From Week 13 to Week 26 | Durability of the therapeutic effect of 6R-BH4 on global function through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. CGI-S is a 7-point scale that requires the clinician to rate the severity of the subject's mental illness at the time of assessment, relative to clinician's past experience with subjects who have the same diagnosis. Considering total clinical experience, a subject is assessed on the severity of mental illness at the time of rating as: 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 6, severely ill; or 7, among the most extremely ill. | Week 13 to Week 26 | 
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Week 13 to Week 26 | Durability of the therapeutic effect of 6R-BH4 on executive function through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. The scoring for the GEC T Score is complex and is achieved using proprietary software designed to generate scores based on raw data collected. Higher scores suggest a higher level of dysfunction. | Week 13 to Week 26 | 
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Week 13 to Week 26 | Durability of the therapeutic effect of 6R-BH4 on executive function through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. The scoring for the GEC T Score is complex and is achieved using proprietary software designed to generate scores based on raw data collected. Higher scores suggest a higher level of dysfunction. | Week 13 to Week 26 | 
| Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 26 | Durability of the therapeutic effect of 6R-BH4 on ADHD through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. The total ADHD-RS score and the corrected total ARS score range from 0 to 54, with higher scores corresponding to worse severity of ADHD symptoms. | Baseline to Week 26 | 
| Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 26 | Durability of the therapeutic effect of 6R-BH4 on anxiety through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. HAM-A Score is a total score ranging from 0 to 56 with higher scores corresponding to worse severity of anxiety symptoms. The HAM-A has 14 items, each measuring specific anxiety symptom clusters. Each item is given a 5-point-score as: 0, absent; 1, mild; 2, moderate; 3, severe; or 4, incapacitating. | Baseline to Week 26 | 
| Change in Hamilton Rating Scale For Depression (HAM-D) Score From Baseline to Week 26 | Durability of the therapeutic effect of 6R-BH4 on depression through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. HAM-D Score is a total score ranging from 0 to 48 with higher scores corresponding to worse severity of depression. The HAM-D is a 17-item depression rating scale. Nine of the items are scored on a 5-point scale as: 0, absence of depressive symptom being measured; 1, doubt concerning the presence of the symptom; 2, mild symptoms; 3, moderate symptoms; or 4, severe symptoms. The remaining 8 items are scored on a 3-point scale as: 0, absence; 1, doubt on the presence of the symptom; or 2, clear presence of symptoms. | Baseline to Week 26 | 
| Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 26 | Durability of the therapeutic effect of 6R-BH4 on global function through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. CGI-S is a 7-point scale that requires the clinician to rate the severity of the subject's mental illness at the time of assessment, relative to clinician's past experience with subjects who have the same diagnosis. Considering total clinical experience, a subject is assessed on the severity of mental illness at the time of rating as: 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 6, severely ill; or 7, among the most extremely ill. | Baseline to Week 26 | 
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 26 | Durability of the therapeutic effect of 6R-BH4 on executive function through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. The scoring for the GEC T Score is complex and is achieved using proprietary software designed to generate scores based on raw data collected. Higher scores suggest a higher level of dysfunction. | Baseline to Week 26 | 
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 26 | Durability of the therapeutic effect of 6R-BH4 on executive function through 26 weeks in subjects who had a blood Phe level reduction after treatment with 6R-BH4. The scoring for the GEC T Score is complex and is achieved using proprietary software designed to generate scores based on raw data collected. Higher scores suggest a higher level of dysfunction. | Baseline to Week 26 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phenylketonuria, PKU, Kuvan, Sapropterin dihydrochloride, Neuropsychiatric disorder, ADHD