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

This study has been completed.
Information provided by (Responsible Party):
BioMarin Pharmaceutical Identifier:
First received: April 27, 2010
Last updated: July 17, 2013
Last verified: July 2013
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.

Condition Intervention Phase
Drug: Sapropterin dihydrochloride
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-blind, Placebo-controlled, Randomized Study to Evaluate the Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Subjects With Phenylketonuria

Resource links provided by NLM:

Further study details as provided by BioMarin Pharmaceutical:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Assess the safety of sapropterin dihydrochloride when administered as therapy to these patients. [ Time Frame: 26 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 200
Study Start Date: June 2010
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sapropterin dihydrochloride 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
Placebo Comparator: Tablet without active ingredient Drug: Placebo
Placebo (tablet without active ingredient) is dosed once/day for the first 13 weeks of the study.

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.


Ages Eligible for Study:   8 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • ≥ 8 years of age
  • Confirmed diagnosis of PKU
  • Willing to continue current diet (typical diet for the 3 months prior to study entry) unchanged while participating in the study
  • Willing and able to provide written, signed informed consent or in the case of subjects under the age of 18, provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures
  • Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study and for at least 30 days following the last dose of sapropterin dihydrochloride
  • Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have been in menopause at least 2 years, or had tubal ligation at least 1 year prior to screening, or have had total hysterectomy.
  • Willing and able to comply with all study procedure

Exclusion Criteria:

  • Has known hypersensitivity to sapropterin dihydrochloride or its excipients
  • Subject breastfeeding at screening or planning to become pregnant (subject or partner) at any time during the study
  • Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to the completion of all scheduled study assessments
  • Received sapropterin dihydrochloride within 16 weeks of randomization
  • Have initiated or adjusted medication for treatment of ADHD, depression, or anxiety ≤ 8 weeks prior to randomization
  • Taking medication known to inhibit folate synthesis (eg, methotrexate)
  • Any condition requiring treatment with levodopa or any PDE-5 inhibitor
  • Concurrent disease or condition that would interfere with study participation, compliance or safety as determined by the Investigator
  • Any condition that, in the view of the Investigator, places the subject at high risk of poor treatment compliance or of not completing the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01114737

  Show 39 Study Locations
Sponsors and Collaborators
BioMarin Pharmaceutical
Study Director: Suyash Prasad, MD BioMarin Pharmaceutical
  More Information

No publications provided

Responsible Party: BioMarin Pharmaceutical Identifier: NCT01114737     History of Changes
Other Study ID Numbers: PKU-016, PKU Ascend
Study First Received: April 27, 2010
Last Updated: July 17, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by BioMarin Pharmaceutical:
Sapropterin dihydrochloride
Neuropsychiatric disorder

Additional relevant MeSH terms:
Amino Acid Metabolism, Inborn Errors
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases
Anti-Arrhythmia Agents
Calcium Channel Blockers
Cardiovascular Agents
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Vasodilator Agents processed this record on November 30, 2015