Safety and Efficacy Study of Phenoptin in Subjects With Hyperphenylalaninemia Due to BH4 Deficiency

Brief Title

Safety and Efficacy Study of Phenoptin in Subjects With Hyperphenylalaninemia Due to BH4 Deficiency

Official Title

Phase 2, Multicenter, Open Label Study of Phenoptin in Subjects With Hyperphenylalaninemia Due to Primary BH4 Deficiency

Brief Summary

      The purpose of this study is to evaluate the ability of Phenoptin to control blood
      phenylalanine levels in subjects who have hyperphenylalaninemia due to a primary BH4
      deficiency and to evaluate the safety of Phenoptin in this population. Some subjects were
      receiving non-registered formulations of BH4 at enrollment and this treatment was suspended
      after Part 1 and within one day the subjects started Phenoptin at approximately the same
      dose.
    

Detailed Description

      Within 4 weeks of completing screening assessments to determine eligibility, subjects will be
      enrolled in the study. The study will be conducted in two parts.

      Part 1: After screening, all subjects will be followed for two weeks without modification of
      their baseline medical or dietary care.

      Part 2: Beginning at Week 2, subjects who were receiving non-registered formulations of BH4
      at enrollment will suspend this treatment and within one day will start Phenoptin at
      approximately the same dose of the non-registered BH4 formulation. Subjects not receiving BH4
      at enrollment will begin treatment with Phenoptin at approximately 5 mg/kg/day, given orally,
      prior to meals.

      At the discretion of the Investigator, the Phenoptin dose may be adjusted up or down at the
      Week 6 visit to control blood Phe levels (<360 µmol/L), or to optimize the clinical effect.
      The maximum dose allowed will be approximately 20 mg/kg/day. All subjects will receive
      Phenoptin for a total of 8 weeks. Subjects will be instructed to continue their usual diet
      without modification. Study visits will occur every other week.

      Tyrosine, biopterin and neopterin will be analyzed at the following visits: Week 0
      (enrollment), Week 2 (prior to dosing with Phenoptin), Week 8 (after 6 weeks of treatment
      with Phenoptin) and Week 10 (after 8 weeks of treatment with Phenoptin).During each visit,
      blood Phe level will be measured (2.5-5 hours after a meal), and safety evaluations will be
      performed. Safety will be assessed by monitoring adverse events and vital signs, performing
      physical examinations, assessing signs and symptoms of primary BH4 deficiency (i.e.,
      neurological symptoms such as seizures, changes in muscle tone, weakness, etc.) and clinical
      laboratory tests (chemistry, hematology and urinalysis).

      Extension: Upon completion of 8 weeks of treatment (i.e., at the Week 10 visit), subjects
      will be offered the option to continue treatment with Phenoptin in an extension of this
      study. Participation in the study extension will continue until one of the following occurs:

        1. the subject withdraws consent and discontinues from the study,

        2. the subject is discontinued from the study at the discretion of the investigator,

        3. the study drug is available through the appropriate marketing approval, or

        4. the study is terminated.

      During the extension period, study drug will be dispensed to subjects monthly, and study
      visits will be required every 3 months. The Phenoptin dose may be adjusted at any visit
      during the study extension at the discretion of the Investigator. The maximum dose allowed
      will be approximately 20 mg/kg/day.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Blood Phenylalanine(Phe) Levels Measured at Specified Timepoints

Secondary Outcome

 Subjects Experiencing Adverse Events(AEs)

Condition

Tetrahydrobiopterin Deficiencies

Intervention

Phenoptin

Study Arms / Comparison Groups

 Single Arm on Active Drug
Description:  5mg/kg/day orally, dose may be adjusted to between 5-20 mg/kg/day by investigator at week 6 to control blood Phe levels
Outcomes were also evaluated by the subject's type of BH4 deficiency either defects in the genes encoding the enzymes involved in biosynthesis or defects in the genes encoding the enzymes involved in recycling.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

12

Start Date

August 2006

Completion Date

June 2009

Primary Completion Date

June 2009

Eligibility Criteria

        Inclusion Criteria:

          -  Documented history of blood Phe level > 180 µmol/L on at least one occasion

          -  Established diagnosis of hyperphenylalaninemia (HPA) due to primary BH4 deficiency
             with a documented defect in biopterin metabolism with blood or urine tests

          -  Willing and able to provide written informed consent or, in the case of subjects under
             the age of 18 years, provide written assent (if required) and written informed consent
             by a parent or legal guardian

          -  Negative urine pregnancy test at screening for females of child-bearing potential

          -  Male and female subjects of childbearing potential (if sexually active and
             non-sterile) must be using acceptable birth control measures and be willing to
             continue to use acceptable birth control measures, as determined by the Investigator,
             and be willing to continue to use acceptable birth control measures while
             participating in the study

          -  Willing and able to comply with all study procedures

          -  Able to take medication orally

        Exclusion Criteria:

          -  Perceived to be unreliable or unavailable for study participation or, if under the age
             of 18 years, have parents or legal guardians who are perceived to be unreliable or
             unavailable

          -  Use of any investigational agent (other than BH4) within 30 days prior to screening,
             or requirement for any investigational agent or vaccine prior to completion of all
             scheduled study assessments

          -  Positive urine pregnancy test at screening (non-sterile females of child bearing
             potential only), already known to be pregnant or breastfeeding or planning a pregnancy
             in self or partner during the study

          -  Female subjects of childbearing potential not using an effective method of birth
             control, as determined by the PI, or unwilling to continue to use acceptable birth
             control measures.

          -  Alanine aminotransferase (ALT) > 2 times the upper limit of normal (i.e., Grade 1 or
             higher based on World Health Organization Toxicity Criteria) at screening

          -  Concurrent disease or condition that would interfere with study participation or
             safety (e.g., seizure disorder, oral steroid-dependent asthma or other condition
             requiring oral or parenteral corticosteroid administration, insulin-dependent
             diabetes, or organ transplantation)

          -  Serious neuropsychiatric illness (e.g., major depression) not currently under medical
             control

          -  Requirement for concomitant treatment with any drug known to inhibit folate synthesis
             (e.g., methotrexate)

          -  Clinical diagnosis of phenylketonuria (PKU) due to phenylalanine hydroxylase
             deficiency

          -  Any condition that, in the view of the PI, renders the subject at high risk from
             treatment compliance and/or completing the study
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT00355264

Organization ID

PKU-007


Responsible Party

Sponsor

Study Sponsor

BioMarin Pharmaceutical


Study Sponsor

, , 


Verification Date

September 2020