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

NCT01114737 | Completed Phase 3 Results DMC

• 2 other identifiers: PKU-016PKU Ascend
• Study Type: interventional
• Target: 206
• Locations: 2 countries
• Sites: 36

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.

Conditions

Phenylketonuria

Keywords

Phenylketonuria; PKU; Kuvan; Sapropterin dihydrochloride; Neuropsychiatric disorder; ADHD

Outcome Measures

Primary Outcomes (2)

• Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From Baseline to Week 13

  Effects of 6R-BH4 on symptoms of ADHD in PKU subjects who had symptoms of ADHD at screening in the subjects that had a blood Phe level reduction after treatment with 6R-BH4. The total ADHD-RS score and the corrected total ARS score range from 0 to 54, with higher scores corresponding to worse severity of ADHD symptoms.

  Baseline to Week 13

• Number of Participants With a Score of 1 or 2 in Global Function Evaluation (CGI-I) From Baseline to Week 13.

  Effects of 6R-BH4 on global function in PKU subjects in subjects that had a blood Phe level reduction after treatment with 6R-BH4 at screening. The CGI-I is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.

  13 weeks

Secondary Outcomes (17)

• Change in Hamilton Anxiety Rating Scale (HAM-A) Score From Baseline to Week 13

  Baseline to Week 13

• Change in Hamilton Depression Rating Scale (HAM-D) Score From Baseline to Week 13

  Baseline to Week 13

• Change in Clinical Global Impression-Severity (CGI-S) From Baseline to Week 13

  Baseline to Week 13

• Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From Baseline to Week 13

  Baseline to Week 13

• Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From Baseline to Week 13

  Baseline to Week 13

Study Arms (2)

Sapropterin dihydrochloride

EXPERIMENTAL

Drug: Sapropterin dihydrochloride

Tablet without active ingredient

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Sapropterin dihydrochloride DRUG

A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact).

Also known as: Kuvan, Phenoptin, BH4, 6R BH4

Sapropterin dihydrochloride

Placebo DRUG

Placebo (tablet without active ingredient) is dosed once/day for the first 13 weeks of the study.

Tablet without active ingredient

Eligibility Criteria

• Age: 8 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 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

You may not qualify if:

• 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

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (36)

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La Jolla, California, United States

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Los Angeles, California, United States

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Palo Alto, California, United States

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San Francisco, California, United States

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Aurora, Colorado, United States

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Washington D.C., District of Columbia, United States

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Gainesville, Florida, United States

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Tampa, Florida, United States

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Atlanta, Georgia, United States

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Chicago, Illinois, United States

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Indianapolis, Indiana, United States

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Boston, Massachusetts, United States

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Minneapolis, Minnesota, United States

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Albany, New York, United States

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Buffalo, New York, United States

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Rochester, New York, United States

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Chapel Hill, North Carolina, United States

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Cleveland, Ohio, United States

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Portland, Oregon, United States

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Hershey, Pennsylvania, United States

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Philadelphia, Pennsylvania, United States

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Pittsburgh, Pennsylvania, United States

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Nashville, Tennessee, United States

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Dallas, Texas, United States

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Madison, Wisconsin, United States

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Milwaukee, Wisconsin, United States

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Calgary, Alberta, Canada

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Edmonton, Alberta, Canada

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Vancouver, British Columbia, Canada

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Winnipeg, Manitoba, Canada

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Halifax, Nova Scotia, Canada

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Hamilton, Ontario, Canada

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Kingston, Ontario, Canada

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London, Ontario, Canada

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Toronto, Ontario, Canada

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Montreal, Quebec, Canada

Location

Related Publications (1)

• Grant ML, Jurecki ER, McCandless SE, Stahl SM, Bilder DA, Sanchez-Valle A, Dimmock D. Neuropsychiatric Function Improvement in Pediatric Patients with Phenylketonuria. J Pediatr. 2023 Sep;260:113526. doi: 10.1016/j.jpeds.2023.113526. Epub 2023 May 30.

  PMID: 37263523 DERIVED

MeSH Terms

Conditions

Phenylketonurias; Attention Deficit Disorder with Hyperactivity

Interventions

sapropterin; phenoptin

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders

Limitations and Caveats

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

Results Point of Contact

• Title: Medical Information Services
• Organization: BioMarin Pharmaceutical Inc.

medinfo@bmrn.com

1-800-983-4587

Study Officials

• Suyash Prasad, MD

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2010
• First Posted: May 3, 2010
• Study Start: August 1, 2010
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: February 1, 2016
• Results First Posted: February 1, 2016

Record last verified: 2015-12

Locations

CA (10); US (26)