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

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ClinicalTrials.gov Identifier: NCT01114737
Recruitment Status : Completed
First Posted : May 3, 2010
Results First Posted : February 1, 2016
Last Update Posted : February 1, 2016
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Phenylketonuria
Interventions Drug: Sapropterin dihydrochloride
Drug: Placebo
Enrollment 206
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo 6R-BH4 20 mg/kg/Day
Hide Arm/Group Description 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). 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
Period Title: Randomized Treatment Period
Started 108 98
Completed 105 97
Not Completed 3 1
Reason Not Completed
Withdrawal by Subject             1             0
Lost to Follow-up             1             1
Pregnancy             1             0
Period Title: Open-Label Treatment Period
Started 105 [1] 97 [2]
Completed 100 95
Not Completed 5 2
Reason Not Completed
Withdrawal by Subject             1             1
Lost to Follow-up             3             1
Difficult Personal Events             1             0
[1]
One subject did not receive a single dose of the study drug
[2]
Two subjects did not receive a single dose of the study drug
Arm/Group Title Placebo 6R-BH4 20 mg/kg/Day Total
Hide Arm/Group Description 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). 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 Total of all reporting groups
Overall Number of Baseline Participants 108 98 206
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 108 participants 98 participants 206 participants
22.5  (10.42) 23.6  (12.69) 23.1  (11.54)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 108 participants 98 participants 206 participants
<18 years 43 43 86
>=18 years 65 55 120
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 108 participants 98 participants 206 participants
Female
54
  50.0%
41
  41.8%
95
  46.1%
Male
54
  50.0%
57
  58.2%
111
  53.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 108 participants 98 participants 206 participants
Hispanic or Latino
3
   2.8%
5
   5.1%
8
   3.9%
Not Hispanic or Latino
105
  97.2%
93
  94.9%
198
  96.1%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 108 participants 98 participants 206 participants
American Indian or Alaska Native 1 0 1
Asian 1 1 2
Native Hawaiian or Other Pacific Islander 0 0 0
Black or African American 2 0 2
White 102 96 198
Other 2 1 3
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 108 participants 98 participants 206 participants
Canada 38 31 69
United States 70 67 137
1.Primary Outcome
Title Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 13
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Responders in Placebo Arm With ADHD Symptoms Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment with ADHD symptoms at Baseline
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment with ADHD symptoms at Baseline
Overall Number of Participants Analyzed 19 19
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-4.9
(-8.9 to -0.9)
-9.1
(-13.5 to -4.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm With ADHD Symptoms, Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.085
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for baseline ADHD-RS/ASRS total score, age group, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.2
Confidence Interval (2-Sided) 95%
-8.9 to 0.6
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.3
Estimation Comments [Not Specified]
2.Primary Outcome
Title Number of Participants With a Score of 1 or 2 in Global Function Evaluation (CGI-I) From Baseline to Week 13.
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Missing data for 1 subject in the Responders in 6R-BH4 20 mg/kg/day Arm
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 60
Measure Type: Number
Unit of Measure: Number of participants with scale 1 or 2
15 13
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.67
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Adjusted for age group, ADHD symptom, and ADHD medication
Method of Estimation Estimation Parameter Relative Risk
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.46 to 1.64
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 13
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 61
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-3.6
(-5.4 to -1.9)
-3.2
(-5.1 to -1.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.669
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for baseline HAMA Anxiety Scale Total Score, age group, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-1.5 to 2.3
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.9
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change in Hamilton Depression Rating Scale (HAM-D) Score From Baseline to Week 13
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 61
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-2.5
(-3.9 to -1.1)
-2.1
(-3.6 to -0.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.588
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Baseline HAM-D Rating Scale Total Score, age group, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-1.1 to 1.9
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.8
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 13
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Phe Responders
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 61
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-0.5
(-0.8 to -0.2)
-0.6
(-0.9 to -0.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.531
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for baseline CGI-Severity Response, age group, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-0.4 to 0.2
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.2
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 13
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Phe Responders who are >=18 Years of Age
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 28 25
Least Squares Mean (95% Confidence Interval)
Unit of Measure: T score
-8.1
(-12.6 to -3.6)
-9.1
(-14.6 to -3.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.661
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Baseline BRIEF Adult-GEC T Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.0
Confidence Interval (2-Sided) 95%
-5.5 to 3.6
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.2
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 13
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Phe Responders who are <18 Years of Age
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 29 36
Least Squares Mean (95% Confidence Interval)
Unit of Measure: T score
-0.7
(-4.0 to 2.7)
-4.8
(-8.0 to -1.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.034
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Baseline BRIEF Parent-GEC T Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.1
Confidence Interval (2-Sided) 95%
-7.9 to -0.3
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.9
Estimation Comments [Not Specified]
8.Secondary Outcome
Title 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
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Phe Responders with ADHD Symptoms
Arm/Group Title Responders in Placebo Arm With ADHD Symptoms Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment with ADHD symptoms at baseline
Included all subjects in the 6R-BH4 20 mg/kg/day arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment with ADHD symptoms at baseline
Overall Number of Participants Analyzed 19 19
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-4.0
(-8.2 to 0.2)
-1.4
(-6.1 to 3.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm With ADHD Symptoms, Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.312
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Week 13 ADHD RS/ASRS Total Score, age group, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.6
Confidence Interval (2-Sided) 95%
-2.6 to 7.8
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.6
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Week 13 to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Phe Responders
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.1
(-1.7 to 1.8)
-0.5
(-2.3 to 1.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.590
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Week 13 HAMA Anxiety Rating Scale Total Score, age group, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.5
Confidence Interval (2-Sided) 95%
-2.4 to 1.4
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.0
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Change in Hamilton Depression Rating Scale (HAM-D) Score From Week 13 to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Phe Responders
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.1
(-1.3 to 1.5)
0.5
(-1.1 to 2.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.636
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Week 13 HAMD Rating Scale Total Score, age group, ADHD symptom, and ADHD
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-1.2 to 1.9
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.8
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Change in Clinical Global Impression-Severity (CGI-S) From Week 13 to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Phe Responders
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-0.0
(-0.3 to 0.3)
0.1
(-0.2 to 0.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.510
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Week 13 Global Impression-Severity Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.2 to 0.5
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.2
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Week 13 to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Phe Responders who is >=18 Years of Age
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 28 24
Least Squares Mean (95% Confidence Interval)
Unit of Measure: T score
-0.7
(-4.5 to 3.1)
0.9
(-3.7 to 5.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.395
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Week 13 BRIEF Adult-GEC T Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.6
Confidence Interval (2-Sided) 95%
-2.1 to 5.2
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.8
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Week 13 to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Phe Responders who is <18 Years of Age
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 29 36
Least Squares Mean (95% Confidence Interval)
Unit of Measure: T score
-1.3
(-4.3 to 1.7)
0.0
(-2.7 to 2.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.443
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Week 13 BRIEF Parent-GEC T Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.3
Confidence Interval (2-Sided) 95%
-2.1 to 4.7
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.7
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Responders in Placebo Arm With ADHD Symptoms Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment with ADHD symptoms at baseline
Included all subjects in the 6R-BH4 20 mg/kg/day arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment with ADHD symptoms at baseline
Overall Number of Participants Analyzed 19 19
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-9.5
(-14.2 to -4.8)
-9.3
(-14.5 to -4.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm With ADHD Symptoms, Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.953
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Baseline ADHD-RS/ASRS Total Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.2
Confidence Interval (2-Sided) 95%
-5.5 to 5.8
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.8
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 61
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-3.9
(-5.8 to -2.0)
-4.2
(-6.3 to -2.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.733
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Baseline Hamilton Anxiety Rating Scale (HAM-A) Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.4
Confidence Interval (2-Sided) 95%
-2.4 to 1.7
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.0
Estimation Comments [Not Specified]
16.Secondary Outcome
Title Change in Hamilton Rating Scale For Depression (HAM-D) Score From Baseline to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 61
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-2.6
(-4.1 to -1.0)
-2.0
(-3.7 to -0.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.522
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Baseline Hamilton Rating Scale For Depression (HAM-D) Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
-1.1 to 2.2
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.8
Estimation Comments [Not Specified]
17.Secondary Outcome
Title Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 57 61
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-0.6
(-0.9 to -0.3)
-0.5
(-0.8 to -0.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.564
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Baseline Clinical Global Impression-Severity (CGI-S), ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.2 to 0.4
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.2
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 28 25
Least Squares Mean (95% Confidence Interval)
Unit of Measure: T score
-7.1
(-12.6 to -1.6)
-7.7
(-14.5 to -0.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.833
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Baseline BRIEF Adult-GEC T Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.6
Confidence Interval (2-Sided) 95%
-6.2 to 5.0
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.8
Estimation Comments [Not Specified]
19.Secondary Outcome
Title Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 26
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Responders in Placebo Arm Responders in 6R-BH4 20 mg/kg/Day Arm
Hide Arm/Group Description:
Included all subjects in the Placebo arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment.
Included all subjects in the 6R-BH4 20 mg/kg/day Arm who had a blood Phe level reduction ≥ 20% from Baseline within their first 4 weeks of sapropterin treatment
Overall Number of Participants Analyzed 29 36
Least Squares Mean (95% Confidence Interval)
Unit of Measure: T score
-2.6
(-6.2 to 1.0)
-4.8
(-8.2 to -1.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders in Placebo Arm, Responders in 6R-BH4 20 mg/kg/Day Arm
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.279
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for Baseline BRIEF Parent-GEC T Score, ADHD symptom, and ADHD medication.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.2
Confidence Interval (2-Sided) 95%
-6.3 to 1.8
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.0
Estimation Comments [Not Specified]
Time Frame Study Period
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Randomized Treatment Period - Placebo Randomized Treatment Period - 6R-BH4 Randomized Treatment Period - Overall Open-Label Treatment Period - Placebo-6R-BH4 Open-Label Treatment Period - 6R-BH4 Open-Label Treatment Period - Overall 6R-BH4 Treatment Period - 6R-BH4 6R-BH4 Treatment Period - Combined
Hide Arm/Group Description Randomized Treatment Period - Placebo: Placebo (tablet without active ingredient) is dosed once/day for the first 13 weeks of the study. Randomized Treatment Period - Sapropterin dihydrochloride: A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact). Randomized Treatment Period - All patients Open-label Treatment Period - Placebo: Placebo (tablet without active ingredient) is dosed once/day for the first 13 weeks of the study. Open-label Treatment Period - Sapropterin dihydrochloride: A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact). Open-label Treatment Period - All patients 6R-BH4 Treatment Period - Sapropterin dihydrochloride: A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact). 6R-BH4 Combined Treatments - Sapropterin dihydrochloride: A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact).
All-Cause Mortality
Randomized Treatment Period - Placebo Randomized Treatment Period - 6R-BH4 Randomized Treatment Period - Overall Open-Label Treatment Period - Placebo-6R-BH4 Open-Label Treatment Period - 6R-BH4 Open-Label Treatment Period - Overall 6R-BH4 Treatment Period - 6R-BH4 6R-BH4 Treatment Period - Combined
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Randomized Treatment Period - Placebo Randomized Treatment Period - 6R-BH4 Randomized Treatment Period - Overall Open-Label Treatment Period - Placebo-6R-BH4 Open-Label Treatment Period - 6R-BH4 Open-Label Treatment Period - Overall 6R-BH4 Treatment Period - 6R-BH4 6R-BH4 Treatment Period - Combined
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/108 (2.78%)      0/98 (0.00%)      3/206 (1.46%)      2/104 (1.92%)      0/95 (0.00%)      2/199 (1.01%)      0/98 (0.00%)      2/202 (0.99%)    
Infections and infestations                 
Necrotising fasciitis  1  1/108 (0.93%)  1 0/98 (0.00%)  0 1/206 (0.49%)  1 0/104 (0.00%)  0 0/95 (0.00%)  0 0/199 (0.00%)  0 0/98 (0.00%)  0 0/202 (0.00%)  0
Injury, poisoning and procedural complications                 
Animal bite  1  0/108 (0.00%)  0 0/98 (0.00%)  0 0/206 (0.00%)  0 1/104 (0.96%)  1 0/95 (0.00%)  0 1/199 (0.50%)  1 0/98 (0.00%)  0 1/202 (0.50%)  1
Concussion  1  1/108 (0.93%)  1 0/98 (0.00%)  0 1/206 (0.49%)  1 0/104 (0.00%)  0 0/95 (0.00%)  0 0/199 (0.00%)  0 0/98 (0.00%)  0 0/202 (0.00%)  0
Investigations                 
Amino acid level increased  1  1/108 (0.93%)  1 0/98 (0.00%)  0 1/206 (0.49%)  1 0/104 (0.00%)  0 0/95 (0.00%)  0 0/199 (0.00%)  0 0/98 (0.00%)  0 0/202 (0.00%)  0
Nervous system disorders                 
Petit mal epilepsy  1  0/108 (0.00%)  0 0/98 (0.00%)  0 0/206 (0.00%)  0 1/104 (0.96%)  1 0/95 (0.00%)  0 1/199 (0.50%)  1 0/98 (0.00%)  0 1/202 (0.50%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Randomized Treatment Period - Placebo Randomized Treatment Period - 6R-BH4 Randomized Treatment Period - Overall Open-Label Treatment Period - Placebo-6R-BH4 Open-Label Treatment Period - 6R-BH4 Open-Label Treatment Period - Overall 6R-BH4 Treatment Period - 6R-BH4 6R-BH4 Treatment Period - Combined
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   80/108 (74.07%)      79/98 (80.61%)      159/206 (77.18%)      79/104 (75.96%)      71/95 (74.74%)      150/199 (75.38%)      86/98 (87.76%)      165/202 (81.68%)    
Gastrointestinal disorders                 
Abdominal pain upper  1  5/108 (4.63%)  5 4/98 (4.08%)  5 9/206 (4.37%)  10 2/104 (1.92%)  2 7/95 (7.37%)  7 9/199 (4.52%)  9 9/98 (9.18%)  12 11/202 (5.45%)  14
Diarrhoea  1  4/108 (3.70%)  5 10/98 (10.20%)  12 14/206 (6.80%)  17 8/104 (7.69%)  8 4/95 (4.21%)  6 12/199 (6.03%)  14 13/98 (13.27%)  18 21/202 (10.40%)  26
Nausea  1  10/108 (9.26%)  10 4/98 (4.08%)  5 14/206 (6.80%)  15 10/104 (9.62%)  11 7/95 (7.37%)  7 17/199 (8.54%)  18 10/98 (10.20%)  12 20/202 (9.90%)  23
Vomiting  1  14/108 (12.96%)  14 4/98 (4.08%)  5 18/206 (8.74%)  19 12/104 (11.54%)  15 3/95 (3.16%)  6 15/199 (7.54%)  21 6/98 (6.12%)  11 18/202 (8.91%)  26
General disorders                 
Pyrexia  1  5/108 (4.63%)  5 1/98 (1.02%)  1 6/206 (2.91%)  6 5/104 (4.81%)  5 7/95 (7.37%)  7 12/199 (6.03%)  12 8/98 (8.16%)  8 13/202 (6.44%)  13
Infections and infestations                 
Nasopharyngitis  1  9/108 (8.33%)  10 11/98 (11.22%)  13 20/206 (9.71%)  23 12/104 (11.54%)  13 11/95 (11.58%)  11 23/199 (11.56%)  24 19/98 (19.39%)  24 31/202 (15.35%)  37
Upper respiratory tract infection  1  7/108 (6.48%)  7 4/98 (4.08%)  5 11/206 (5.34%)  12 10/104 (9.62%)  11 3/95 (3.16%)  4 13/199 (6.53%)  15 7/98 (7.14%)  9 17/202 (8.42%)  20
Musculoskeletal and connective tissue disorders                 
Back pain  1  1/108 (0.93%)  1 2/98 (2.04%)  2 3/206 (1.46%)  3 4/104 (3.85%)  4 4/95 (4.21%)  5 8/199 (4.02%)  9 6/98 (6.12%)  7 10/202 (4.95%)  11
Pain in extremity  1  3/108 (2.78%)  3 1/98 (1.02%)  2 4/206 (1.94%)  5 3/104 (2.88%)  3 7/95 (7.37%)  9 10/199 (5.03%)  12 8/98 (8.16%)  11 11/202 (5.45%)  14
Nervous system disorders                 
Headache  1  28/108 (25.93%)  37 25/98 (25.51%)  51 53/206 (25.73%)  88 16/104 (15.38%)  21 17/95 (17.89%)  30 33/199 (16.58%)  51 32/98 (32.65%)  81 48/202 (23.76%)  102
Respiratory, thoracic and mediastinal disorders                 
Cough  1  8/108 (7.41%)  8 7/98 (7.14%)  7 15/206 (7.28%)  15 8/104 (7.69%)  8 8/95 (8.42%)  10 16/199 (8.04%)  18 10/98 (10.20%)  17 18/202 (8.91%)  25
Nasal congestion  1  11/108 (10.19%)  12 7/98 (7.14%)  10 18/206 (8.74%)  22 4/104 (3.85%)  5 12/95 (12.63%)  15 16/199 (8.04%)  20 17/98 (17.35%)  25 21/202 (10.40%)  30
Oropharyngeal pain  1  10/108 (9.26%)  10 6/98 (6.12%)  6 16/206 (7.77%)  16 11/104 (10.58%)  11 11/95 (11.58%)  13 22/199 (11.06%)  24 16/98 (16.33%)  19 27/202 (13.37%)  30
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
As specified in the SAP, no multiplicity adjustment was made in the analyses; therefore, the family-wise error rate was not controlled in this study
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Information Services
Organization: BioMarin Pharmaceutical Inc.
Phone: 1-800-983-4587
EMail: medinfo@bmrn.com
Layout table for additonal information
Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT01114737     History of Changes
Other Study ID Numbers: PKU-016
PKU Ascend ( Other Identifier: BioMarin Pharmaceutical )
First Submitted: April 27, 2010
First Posted: May 3, 2010
Results First Submitted: August 19, 2015
Results First Posted: February 1, 2016
Last Update Posted: February 1, 2016