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PhenylketonuriaPhase 3NCT01114737

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

A Phase 3 study testing Sapropterin dihydrochloride in people with Phenylketonuria, run by BioMarin Pharmaceutical at 36 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 8 to 65 years
Conditions the study is for
Phenylketonuria
What is being tested?
Sapropterin dihydrochloride
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
206 participants
Where
36 sitesin 2 countries
Study dates
Aug 2010to Mar 2013
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 8 to 65 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • ≥ 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

Who cannot join

  • 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)
Show all 9Show fewer
  • 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

Trial locations and contacts

36 sites in 2 countries.

36 sites in 2 countries

United States26 sites
  • Study site

    Albany, New York

  • Study site

    Atlanta, Georgia

  • Study site

    Aurora, Colorado

  • Study site

    Boston, Massachusetts

  • Study site

    Buffalo, New York

  • Study site

    Chapel Hill, North Carolina

  • Study site

    Chicago, Illinois

  • Study site

    Cleveland, Ohio

  • Study site

    Dallas, Texas

  • Study site

    Gainesville, Florida

  • Study site

    Hershey, Pennsylvania

  • Study site

    Indianapolis, Indiana

  • Study site

    La Jolla, California

  • Study site

    Los Angeles, California

  • Study site

    Madison, Wisconsin

  • Study site

    Milwaukee, Wisconsin

  • Study site

    Minneapolis, Minnesota

  • Study site

    Nashville, Tennessee

  • Study site

    Palo Alto, California

  • Study site

    Philadelphia, Pennsylvania

  • Study site

    Pittsburgh, Pennsylvania

  • Study site

    Portland, Oregon

  • Study site

    Rochester, New York

  • Study site

    San Francisco, California

  • Study site

    Tampa, Florida

  • Study site

    Washington D.C., District of Columbia

Other trials in United States

Canada10 sites
  • Study site

    Calgary, Alberta

  • Study site

    Edmonton, Alberta

  • Study site

    Halifax, Nova Scotia

  • Study site

    Hamilton, Ontario

  • Study site

    Kingston, Ontario

  • Study site

    London, Ontario

  • Study site

    Montreal, Quebec

  • Study site

    Toronto, Ontario

  • Study site

    Vancouver, British Columbia

  • Study site

    Winnipeg, Manitoba

Other trials in Canada

About this study

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

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.

Read the 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.

Conditions
Phenylketonuria
Being tested
Sapropterin dihydrochloride, Placebo
Keywords
Phenylketonuria, PKU, Kuvan, Sapropterin dihydrochloride, Neuropsychiatric disorder, ADHD
Medical subject headings
Phenylketonurias, Attention Deficit Disorder with Hyperactivity

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Sapropterin dihydrochlorideDrug

    Also called Kuvan, Phenoptin, BH4, 6R BH4

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

  • PlaceboDrug

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

Study groups in NCT01114737
Study groupRoleWhat they receive
Sapropterin dihydrochlorideExperimentalNot described
Receives: Drug: Sapropterin dihydrochloride
Tablet without active ingredientPlacebo comparatorNot described
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline to Week 13

  2. 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.

    Measured: 13 weeks

Secondary outcomes (17)
  1. Change in Hamilton Anxiety Rating Scale (HAM-A) Score From 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.

    Measured: Baseline to Week 13

  2. Change in Hamilton Depression Rating Scale (HAM-D) Score From 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.

    Measured: Baseline to Week 13

  3. Change in Clinical Global Impression-Severity (CGI-S) From 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.

    Measured: Baseline to Week 13

  4. Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From 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.

    Measured: Baseline to Week 13

  5. Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From 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.

    Measured: Baseline to Week 13

  6. 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

    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.

    Measured: Week 13 to Week 26

  7. Change in Hamilton Anxiety Rating Scale (HAM-A) Score From 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.

    Measured: Week 13 to Week 26

  8. Change in Hamilton Depression Rating Scale (HAM-D) Score From 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.

    Measured: Week 13 to Week 26

  9. Change in Clinical Global Impression-Severity (CGI-S) From 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.

    Measured: Week 13 to Week 26

  10. Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From 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.

    Measured: Week 13 to Week 26

  11. Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From 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.

    Measured: Week 13 to Week 26

  12. Change in Attention-Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS) / Adult ADHD Self-Report Scale (ASRS) Total Score From 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.

    Measured: Baseline to Week 26

  13. Change in Hamilton Anxiety Rating Scale (HAM-A) Score From 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.

    Measured: Baseline to Week 26

  14. Change in Hamilton Rating Scale For Depression (HAM-D) Score From 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.

    Measured: Baseline to Week 26

  15. Change in Clinical Global Impression-Severity (CGI-S) From 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.

    Measured: Baseline to Week 26

  16. Change in Behavior Rating Inventory of Executive Function (BRIEF) Adult-Global Executive Composite (GEC) T Score From 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.

    Measured: Baseline to Week 26

  17. Change in Behavior Rating Inventory of Executive Function (BRIEF) Parent-Global Executive Composite (GEC) T Score From 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.

    Measured: Baseline to Week 26

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 May 2010 (estimated)
  2. Study startAug 2010
  3. Primary completionMar 2013
  4. Study completionMar 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
206 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01114737
Sponsor's protocol ID
PKU-016
Other IDs
PKU Ascend
Status last verified
Dec 2015
First submitted
27 Apr 2010
Last updated
1 Feb 2016
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 37263523

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Sapropterin dihydrochloride in people with Phenylketonuria, run by BioMarin Pharmaceutical at 36 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 36 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Feb 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01114737, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2016.

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