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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

Tracking Information
First Submitted Date  ICMJE April 27, 2010
First Posted Date  ICMJE May 3, 2010
Results First Submitted Date  ICMJE August 19, 2015
Results First Posted Date  ICMJE February 1, 2016
Last Update Posted Date February 1, 2016
Study Start Date  ICMJE August 2010
Actual Primary Completion Date March 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 24, 2015)
  • Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 13 [ Time Frame: 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. [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 30, 2010)
Evaluate the therapeutic effects of sapropterin dihydrochloride on the symptoms of ADHD and on global function compared to placebo, in subjects with a blood Phe level reduction after treatment. [ Time Frame: 13 weeks ]
ADHD change will be measured as a change in ADHD from baseline to week 13 using the Attention-Deficit Hyperactivity Disorder Rating Scale and Adult ADHD Self-Report Scale (ADHD RS/ASRS) measurement. Global function will be measured as a change in global function using the Clinical Global Impression-Improvement (CGI-I) scale rating compared from baseline to week 13.
Change History Complete list of historical versions of study NCT01114737 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 24, 2015)
  • Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 13 [ Time Frame: 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 Hamilton Depression Rating Scale (HAM-D) Score From Baseline to Week 13 [ Time Frame: 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.
  • Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 13 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Week 13 to Week 26 [ Time Frame: 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 Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Week 13 to Week 26 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2010)
  • Evaluate the therapeutic effects of sapropterin dihydrochloride on the symptoms of anxiety and depression compared to placebo, in subjects with a blood Phe level reduction after treatment. [ Time Frame: 13 weeks ]
  • Evaluate the durability of any therapeutic effects of sapropterin dihydrochloride on neuropsychiatric symptoms and global function of subjects who have a blood Phe level reduction after treatment. [ Time Frame: 26 weeks ]
  • Determine if sapropterin dihydrochloride has a therapeutic effect on neuropsychiatric symptoms in PKU patients who do not have a blood Phe reduction after treatment. [ Time Frame: 26 weeks ]
  • Assess the safety of sapropterin dihydrochloride when administered as therapy to these patients. [ Time Frame: 26 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Phenylketonuria (PKU) Patients
Official Title  ICMJE A Double-blind, Placebo-controlled, Randomized Study to Evaluate the Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Subjects With Phenylketonuria
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Phenylketonuria
Intervention  ICMJE
  • Drug: Sapropterin dihydrochloride
    A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact).
    Other Names:
    • Kuvan
    • Phenoptin
    • BH4
    • 6R BH4
  • Drug: Placebo
    Placebo (tablet without active ingredient) is dosed once/day for the first 13 weeks of the study.
Study Arms  ICMJE
  • Experimental: Sapropterin dihydrochloride
    Intervention: Drug: Sapropterin dihydrochloride
  • Placebo Comparator: Tablet without active ingredient
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 24, 2015)
206
Original Estimated Enrollment  ICMJE
 (submitted: April 30, 2010)
200
Actual Study Completion Date  ICMJE March 2013
Actual Primary Completion Date March 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 8 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01114737
Other Study ID Numbers  ICMJE PKU-016
PKU Ascend ( Other Identifier: BioMarin Pharmaceutical )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party BioMarin Pharmaceutical
Study Sponsor  ICMJE BioMarin Pharmaceutical
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Suyash Prasad, MD BioMarin Pharmaceutical
PRS Account BioMarin Pharmaceutical
Verification Date December 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP