Phenylketonuria
Conditions
Keywords
Phenylketonuria, PKU, Kuvan, Sapropterin dihydrochloride, Neuropsychiatric disorder, ADHD
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.
Interventions
A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact).
DRUGPlacebo
Placebo (tablet without active ingredient) is dosed once/day for the first 13 weeks of the study.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 13 | 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. |
| Number of Participants With a Score of 1 or 2 in Global Function Evaluation (CGI-I) From Baseline to Week 13. | 13 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 13 | 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. |
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 13 | 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. |
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 13 | 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. |
| 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 | 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. |
| Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Week 13 to Week 26 | 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. |
| Change in Hamilton Depression Rating Scale (HAM-D) Score From Week 13 to Week 26 | 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. |
| Change in Clinical Global Impression-Severity (CGI-S) From Week 13 to Week 26 | 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. |
| Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 13 | 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. |
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Week 13 to Week 26 | 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. |
| Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 26 | 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. |
| Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 26 | 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. |
| Change in Hamilton Rating Scale For Depression (HAM-D) Score From Baseline to Week 26 | 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. |
| Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 26 | 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. |
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 26 | 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. |
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 26 | 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. |
| Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Week 13 to Week 26 | 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. |
| Change in Hamilton Depression Rating Scale (HAM-D) Score From Baseline to Week 13 | 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: Placebo (tablet without active ingredient) is dosed once/day for the first 13 weeks of the study(double-blinded randomized treatment period); then treated with sapropterin dihydrochloride 20 mg/kg/day for an additional 13 weeks (open label treatment period). | 108 |
| 6R-BH4 20 mg/kg/Day Sapropterin dihydrochloride: A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact). Patient will be treated for 26 weeks, the first 13 weeks were double-blinded randomized treatment period, the second 13 weeks open label treatment period | 98 |
| Total | 206 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open-Label Treatment Period | Difficult Personal Events | 1 | 0 |
| Open-Label Treatment Period | Lost to Follow-up | 3 | 1 |
| Open-Label Treatment Period | Withdrawal by Subject | 1 | 1 |
| Randomized Treatment Period | Lost to Follow-up | 1 | 1 |
| Randomized Treatment Period | Pregnancy | 1 | 0 |
| Randomized Treatment Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | 6R-BH4 20 mg/kg/Day | Total |
|---|---|---|---|
| Age, Continuous | 22.5 years STANDARD_DEVIATION 10.42 | 23.6 years STANDARD_DEVIATION 12.69 | 23.1 years STANDARD_DEVIATION 11.54 |
| Age, Customized <18 years | 43 participants | 43 participants | 86 participants |
| Age, Customized >=18 years | 65 participants | 55 participants | 120 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 105 Participants | 93 Participants | 198 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized White | 102 participants | 96 participants | 198 participants |
| Region of Enrollment Canada | 38 participants | 31 participants | 69 participants |
| Region of Enrollment United States | 70 participants | 67 participants | 137 participants |
| Sex: Female, Male Female | 54 Participants | 41 Participants | 95 Participants |
| Sex: Female, Male Male | 54 Participants | 57 Participants | 111 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 80 / 108 | 79 / 98 | 159 / 206 | 79 / 104 | 71 / 95 | 150 / 199 | 86 / 98 | 165 / 202 |
| serious Total, serious adverse events | 3 / 108 | 0 / 98 | 3 / 206 | 2 / 104 | 0 / 95 | 2 / 199 | 0 / 98 | 2 / 202 |
Outcome results
Primary
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.
Time frame: Baseline to Week 13
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 13 | -4.9 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 13 | -9.1 units on a scale |
p-value: 0.08595% CI: [-8.9, 0.6]ANCOVA
Primary
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.
Time frame: 13 weeks
Population: Missing data for 1 subject in the Responders in 6R-BH4 20 mg/kg/day Arm
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Number of Participants With a Score of 1 or 2 in Global Function Evaluation (CGI-I) From Baseline to Week 13. | 15 Number of participants with scale 1 or 2 |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Number of Participants With a Score of 1 or 2 in Global Function Evaluation (CGI-I) From Baseline to Week 13. | 13 Number of participants with scale 1 or 2 |
p-value: 0.6795% CI: [0.46, 1.64]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Baseline to Week 26
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 26 | -9.5 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 26 | -9.3 units on a scale |
p-value: 0.95395% CI: [-5.5, 5.8]ANCOVA
Secondary
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.
Time frame: Week 13 to Week 26
Population: Phe Responders with ADHD Symptoms
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | 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 | -4.0 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | 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 | -1.4 units on a scale |
p-value: 0.31295% CI: [-2.6, 7.8]ANCOVA
Secondary
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.
Time frame: Baseline to Week 13
Population: Phe Responders who are \>=18 Years of Age
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 13 | -8.1 T score |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 13 | -9.1 T score |
p-value: 0.66195% CI: [-5.5, 3.6]ANCOVA
Secondary
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.
Time frame: Baseline to Week 26
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 26 | -7.1 T score |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 26 | -7.7 T score |
p-value: 0.83395% CI: [-6.2, 5]ANCOVA
Secondary
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.
Time frame: Week 13 to Week 26
Population: Phe Responders who is \>=18 Years of Age
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Week 13 to Week 26 | -0.7 T score |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Week 13 to Week 26 | 0.9 T score |
p-value: 0.39595% CI: [-2.1, 5.2]ANCOVA
Secondary
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.
Time frame: Baseline to Week 13
Population: Phe Responders who are \<18 Years of Age
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 13 | -0.7 T score |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 13 | -4.8 T score |
p-value: 0.03495% CI: [-7.9, -0.3]ANCOVA
Secondary
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.
Time frame: Baseline to Week 26
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 26 | -2.6 T score |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 26 | -4.8 T score |
p-value: 0.27995% CI: [-6.3, 1.8]ANCOVA
Secondary
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.
Time frame: Week 13 to Week 26
Population: Phe Responders who is \<18 Years of Age
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Week 13 to Week 26 | -1.3 T score |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Week 13 to Week 26 | 0.0 T score |
p-value: 0.44395% CI: [-2.1, 4.7]ANCOVA
Secondary
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.
Time frame: Baseline to Week 13
Population: Phe Responders
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 13 | -0.5 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 13 | -0.6 units on a scale |
p-value: 0.53195% CI: [-0.4, 0.2]ANCOVA
Secondary
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.
Time frame: Baseline to Week 26
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 26 | -0.6 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 26 | -0.5 units on a scale |
p-value: 0.56495% CI: [-0.2, 0.4]ANCOVA
Secondary
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.
Time frame: Week 13 to Week 26
Population: Phe Responders
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Clinical Global Impression-Severity (CGI-S) From Week 13 to Week 26 | -0.0 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Clinical Global Impression-Severity (CGI-S) From Week 13 to Week 26 | 0.1 units on a scale |
p-value: 0.5195% CI: [-0.2, 0.5]ANCOVA
Secondary
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.
Time frame: Baseline to Week 13
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 13 | -3.6 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 13 | -3.2 units on a scale |
p-value: 0.66995% CI: [-1.5, 2.3]ANCOVA
Secondary
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.
Time frame: Baseline to Week 26
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 26 | -3.9 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 26 | -4.2 units on a scale |
p-value: 0.73395% CI: [-2.4, 1.7]ANCOVA
Secondary
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.
Time frame: Week 13 to Week 26
Population: Phe Responders
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Week 13 to Week 26 | 0.1 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Week 13 to Week 26 | -0.5 units on a scale |
p-value: 0.5995% CI: [-2.4, 1.4]ANCOVA
Secondary
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.
Time frame: Baseline to Week 13
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Hamilton Depression Rating Scale (HAM-D) Score From Baseline to Week 13 | -2.5 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Hamilton Depression Rating Scale (HAM-D) Score From Baseline to Week 13 | -2.1 units on a scale |
p-value: 0.58895% CI: [-1.1, 1.9]ANCOVA
Secondary
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.
Time frame: Week 13 to Week 26
Population: Phe Responders
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Hamilton Depression Rating Scale (HAM-D) Score From Week 13 to Week 26 | 0.1 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Hamilton Depression Rating Scale (HAM-D) Score From Week 13 to Week 26 | 0.5 units on a scale |
p-value: 0.63695% CI: [-1.2, 1.9]ANCOVA
Secondary
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.
Time frame: Baseline to Week 26
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Responders in Placebo Arm With ADHD Symptoms | Change in Hamilton Rating Scale For Depression (HAM-D) Score From Baseline to Week 26 | -2.6 units on a scale |
| Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms | Change in Hamilton Rating Scale For Depression (HAM-D) Score From Baseline to Week 26 | -2.0 units on a scale |
p-value: 0.52295% CI: [-1.1, 2.2]ANCOVA