Trial Outcomes & Findings for Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Phenylketonuria (PKU) Patients (NCT NCT01114737)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

206 participants

Primary outcome timeframe

Baseline to Week 13

Results posted on

2016-02-01

Participant Flow

Participant milestones

Participant milestones
Measure	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).	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
Randomized Treatment Period STARTED	108	98
Randomized Treatment Period COMPLETED	105	97
Randomized Treatment Period NOT COMPLETED	3	1
Open-Label Treatment Period STARTED	105	97
Open-Label Treatment Period COMPLETED	100	95
Open-Label Treatment Period NOT COMPLETED	5	2

Reasons for withdrawal

Reasons for withdrawal
Measure	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).	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
Randomized Treatment Period Withdrawal by Subject	1	0
Randomized Treatment Period Lost to Follow-up	1	1
Randomized Treatment Period Pregnancy	1	0
Open-Label Treatment Period Withdrawal by Subject	1	1
Open-Label Treatment Period Lost to Follow-up	3	1
Open-Label Treatment Period Difficult Personal Events	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=108 Participants 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).	6R-BH4 20 mg/kg/Day n=98 Participants 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 n=206 Participants Total of all reporting groups
Age, Continuous	22.5 years STANDARD_DEVIATION 10.42 • n=5 Participants	23.6 years STANDARD_DEVIATION 12.69 • n=7 Participants	23.1 years STANDARD_DEVIATION 11.54 • n=5 Participants
Age, Customized <18 years	43 participants n=5 Participants	43 participants n=7 Participants	86 participants n=5 Participants
Age, Customized >=18 years	65 participants n=5 Participants	55 participants n=7 Participants	120 participants n=5 Participants
Sex: Female, Male Female	54 Participants n=5 Participants	41 Participants n=7 Participants	95 Participants n=5 Participants
Sex: Female, Male Male	54 Participants n=5 Participants	57 Participants n=7 Participants	111 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	105 Participants n=5 Participants	93 Participants n=7 Participants	198 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized White	102 participants n=5 Participants	96 participants n=7 Participants	198 participants n=5 Participants
Race/Ethnicity, Customized Other	2 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment Canada	38 participants n=5 Participants	31 participants n=7 Participants	69 participants n=5 Participants
Region of Enrollment United States	70 participants n=5 Participants	67 participants n=7 Participants	137 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=19 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=19 Participants 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
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 Interval -8.9 to -0.9	-9.1 units on a scale Interval -13.5 to -4.7

PRIMARY outcome

Timeframe: 13 weeks

Population: Missing data for 1 subject in the Responders in 6R-BH4 20 mg/kg/day Arm

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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=57 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=60 Participants 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
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	13 Number of participants with scale 1 or 2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=57 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=61 Participants 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
Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 13	-3.6 units on a scale Interval -5.4 to -1.9	-3.2 units on a scale Interval -5.1 to -1.4

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=57 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=61 Participants 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
Change in Hamilton Depression Rating Scale (HAM-D) Score From Baseline to Week 13	-2.5 units on a scale Interval -3.9 to -1.1	-2.1 units on a scale Interval -3.6 to -0.6

SECONDARY outcome

Timeframe: Baseline to Week 13

Population: Phe Responders

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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=57 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=61 Participants 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
Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 13	-0.5 units on a scale Interval -0.8 to -0.2	-0.6 units on a scale Interval -0.9 to -0.3

SECONDARY outcome

Timeframe: Baseline to Week 13

Population: Phe Responders who are \>=18 Years of Age

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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=28 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=25 Participants 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
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 Interval -12.6 to -3.6	-9.1 T score Interval -14.6 to -3.5

SECONDARY outcome

Timeframe: Baseline to Week 13

Population: Phe Responders who are \<18 Years of Age

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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=29 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=36 Participants 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
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 Interval -4.0 to 2.7	-4.8 T score Interval -8.0 to -1.6

SECONDARY outcome

Timeframe: Week 13 to Week 26

Population: Phe Responders with ADHD Symptoms

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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=19 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=19 Participants 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
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 Interval -8.2 to 0.2	-1.4 units on a scale Interval -6.1 to 3.3

SECONDARY outcome

Timeframe: Week 13 to Week 26

Population: Phe Responders

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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=57 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=60 Participants 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
Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Week 13 to Week 26	0.1 units on a scale Interval -1.7 to 1.8	-0.5 units on a scale Interval -2.3 to 1.4

SECONDARY outcome

Timeframe: Week 13 to Week 26

Population: Phe Responders

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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=57 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=60 Participants 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
Change in Hamilton Depression Rating Scale (HAM-D) Score From Week 13 to Week 26	0.1 units on a scale Interval -1.3 to 1.5	0.5 units on a scale Interval -1.1 to 2.0

SECONDARY outcome

Timeframe: Week 13 to Week 26

Population: Phe Responders

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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=57 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=60 Participants 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
Change in Clinical Global Impression-Severity (CGI-S) From Week 13 to Week 26	-0.0 units on a scale Interval -0.3 to 0.3	0.1 units on a scale Interval -0.2 to 0.4

SECONDARY outcome

Timeframe: Week 13 to Week 26

Population: Phe Responders who is \>=18 Years of Age

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.

Outcome measures

Outcome measures
Measure	Responders in Placebo Arm With ADHD Symptoms n=28 Participants 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	Responders in 6R-BH4 20 mg/kg/Day Arm With ADHD Symptoms n=24 Participants 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
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 Interval -4.5 to 3.1	0.9 T score Interval -3.7 to 5.4

SECONDARY outcome

Timeframe: Week 13 to Week 26

Population: Phe Responders who is \<18 Years of Age

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.