Dose-Finding Study to Evaluate the Safety, Efficacy, & Tolerability of Multiple Doses of rAvPAL-PEG in Subjects With PKU

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00925054
Recruitment Status : Completed
First Posted : June 19, 2009
Last Update Posted : August 21, 2017
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Brief Summary:
The purpose of this study is to evaluate whether weekly injections of phenylalanine ammonia lyase (rAvPAL-PEG) can reduce blood phenylalanine concentrations in PKU subjects and whether repeated administration is safe.

Condition or disease Intervention/treatment Phase
Phenylketonuria Drug: rAvPAL-PEG Phase 2

Detailed Description:

This is a 2 part, Phase 2, open-label dose-finding study in approximately 35 subjects with PKU. Seven dose cohorts are planned, each consisting of 5 subjects. In Part 1, the planned starting dose levels are those tested in PAL 001 (0.001, 0.003, 0.01, 0.03, 0.1, 0.3, and 1.0 mg/kg), provided no dose limiting toxicity was observed in PAL 001. In Parts 1 and 2, study drug will be administered by clinic staff.

Subjects who completed participation in PAL 001 will receive priority to participate in PAL 002. rAvPAL PEG naïve subjects will be enrolled to fill any dose cohort vacancies resulting from subjects who did not complete PAL 001 or who chose not to continue into PAL 002. In addition, if the number of dose cohorts determined in PAL 001 is less than 7, additional naïve subjects may be added to the existing dose cohorts to provide a total of approximately 35 subjects entering Part 1 of PAL 002. Furthermore, if serial dosing of cohorts in Part 1 of PAL 002 is stopped, additional subjects (either naïve subjects or PAL 001 subjects) may be added to the existing cohorts so that total study enrollment is approximately 35 subjects. In any of these cases, additional subjects will be enrolled sequentially from lowest to highest dose cohort.

Diet will not be altered during the course of this study, except as necessary for safety.

Subjects will be evaluated for safety and for blood Phe concentrations throughout the study. Toxicity will be measured according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.

A Data Monitoring Committee will monitor the study.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2, Open-Label Dose-Finding Study to Evaluate the Safety, Efficacy, and Tolerability of Multiple Subcutaneous (SC) Doses of rAvPAL-PEG in Subjects With PKU
Study Start Date : September 2009
Actual Primary Completion Date : June 2015
Actual Study Completion Date : June 2015

Arm Intervention/treatment
Experimental: rAvPAL-PEG
Subjects will be given rAvPAL-PEG in varying doses not to exceed 5 mg/kg/week until efficacy is reached or until maximum tolerable dose has been reached.
Drug: rAvPAL-PEG
In Part 1, the planned starting dose levels are those tested in PAL-001 (0.001, 0.003, 0.01, 0.03, and 0.1 mg/kg), provided no dose-limiting toxicity was observed in PAL-001. After each subject completes Part 1, the subject's rAvPAL-PEG dosing will continue in Part 2. In Part 2, each subject's dose will be adjusted to attain a target blood Phe concentration with target levels between 120-600 micromol/L and a minimum blood Phe concentration decrease of 30% from baseline.
Other Name: rAvPAL in varying doses determined by safety and efficacy.

Primary Outcome Measures :
  1. Blood Phe concentrations [ Time Frame: Screening, Weeks 1-22 ]

Secondary Outcome Measures :
  1. Safety [ Time Frame: Screening, Weeks 1-22 ]
    Safety will be evaluated on the incidence of AEs and clinically significant changes in vital signs and laboratory test results.

  2. Antibody response [ Time Frame: Periodically throughout the duration of the study (22 weeks) ]
  3. Pharmacokinetics [ Time Frame: Periodically throughout the duration of the study (22 weeks) ]
    Plasma concentrations of rAvPAL-PEG will be measured.

Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 55 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • For subjects who did not participate in PAL-001, diagnosis of PKU with both of the following: Current blood Phe concentration of ≥ 600 mmol/L at Screening and average blood Phe concentration of ≥ 600 µmol/L over the past 3 years, using available data.
  • For subjects who did not participate in PAL-001, evidence that the subject is a non-responder to Kuvan® treatment (ie, 4 weeks of treatment with 20 mg/kg/day of Kuvan®, insufficient response per investigator determination, and treatment end date ≥ 14 days prior to Day 1 [ie, first dose]). Subjects who have had a previous response to Kuvan® treatment but are not currently taking Kuvan® because of noncompliance and have been off treatment for ≥ 6 months prior to Screening are eligible for participation.
  • Willing and able to provide written, signed informed consent, or, in the case of participants under the age of 18, provide written assent (if required) and written informed consent by a parent or legal guardian, after the nature of the study has been explained, and prior to any research-related procedures.
  • Between the ages of 16 and 55 years, inclusive.
  • 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 who have had total hysterectomy.
  • Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study.
  • Maintained a stable diet with no significant modifications during the 4 weeks preceding the administration of study drug.
  • In generally good health as evidenced by physical examination, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and electrocardiogram (ECG) at Screening.
  • Willing and able to comply with study procedures.

Exclusion Criteria:

  • Use of any investigational product (with the exception of rAvPAL-PEG) or investigational medical device within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
  • Use of any medication that is intended to treat PKU within 14 days prior to the administration of study drug.
  • Use or planned use of any injectable drugs containing PEG (other than rAvPAL-PEG), including Depo-Provera, within 3 months prior to Screening and during study participation.
  • A prior reaction that included systemic symptoms (eg, respiratory or gastrointestinal problems, hypotension, angioedema, anaphylaxis) to rAvPAL-PEG or a PEG containing product. Subjects with a prior systemic reaction of generalized rash may be eligible for participation per the discretion of the Principal Investigator in consultation with the Sponsor's Medical Officer.
  • Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) or to breastfeed at any time during the study.
  • Concurrent disease or condition that would interfere with study participation or safety (eg, history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurological, oncologic, or psychiatric disease).
  • Any condition that, in the view of the PI, places the subject at high risk of poor treatment compliance or of not completing the study.
  • Alanine aminotransferase (ALT) concentration > 2 times the upper limit of normal.
  • Creatinine > 1.5 times the upper limit of normal.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00925054

United States, Colorado
The Children's Hospital
Aurora, Colorado, United States, 80045
United States, Georgia
Emory Universty
Decatur, Georgia, United States, 30033
United States, Illinois
Children's Memorial Hospital
Chicago, Illinois, United States, 60614
United States, Minnesota
University of Minnesota Medical Center-Fairview
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington University Center for Applied Research Sciences
Saint Louis, Missouri, United States, 63110
United States, New York
Albany Medical Center
Albany, New York, United States, 12208
Mount Sinai School of Medicine
New York, New York, United States, 10029
United States, Ohio
Akron Children's Hospital
Akron, Ohio, United States, 44308
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
United States, Utah
University of Utah Hospital
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
BioMarin Pharmaceutical
Study Director: Celeste Decker, MD BioMarin Pharmaceutical

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: BioMarin Pharmaceutical Identifier: NCT00925054     History of Changes
Other Study ID Numbers: PAL-002
First Posted: June 19, 2009    Key Record Dates
Last Update Posted: August 21, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by BioMarin Pharmaceutical:

Additional relevant MeSH terms:
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
Metabolic Diseases