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A Study to Evaluate Subcutaneously Administered rAvPAL-PEG in Patients With Phenylketonuria for 24 Weeks

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.
 
ClinicalTrials.gov Identifier: NCT01560286
Recruitment Status : Completed
First Posted : March 22, 2012
Results First Posted : February 27, 2019
Last Update Posted : August 6, 2019
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Tracking Information
First Submitted Date  ICMJE March 5, 2012
First Posted Date  ICMJE March 22, 2012
Results First Submitted Date  ICMJE June 22, 2018
Results First Posted Date  ICMJE February 27, 2019
Last Update Posted Date August 6, 2019
Study Start Date  ICMJE May 2012
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 23, 2019)
Blood Phenylalanine Concentration [ Time Frame: Baseline, Week 24 ]
All patients will have their plasma Phenylalanine (Phe) assessed. Please note that "Pharmacokinetics Sub-study" was not performed, and thus no results are available.
Original Primary Outcome Measures  ICMJE
 (submitted: March 20, 2012)
Phenylalanine reduction [ Time Frame: Weekly Plasma Phe from Weeks 1-24 ]
All patients will be have their plasma Phe assessed weekly from Week 1 through Week 24 of the study.
Change History Complete list of historical versions of study NCT01560286 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 23, 2019)
  • Number of Participants With Study Drug Related Adverse Events [ Time Frame: Minimum Weekly Assessment of Injection Sites, Vital Signs and Adverse Events. Other Safety Assessments will be performed at other intervals (below): ]
  • Percentage of Participants With Positive Anti-PAL Immunoglobulin G [IgG] [ Time Frame: Baseline, Week 24 ]
    Antibody Positivity
  • Trough Concentration of BMN 165 [ Time Frame: Week 1, Week 24 ]
    PK assessment from pre-dose blood draw.
  • Percentage of Participants With Positive Anti-PEG IgG [ Time Frame: Baseline, Week 24 ]
    Antibody Positivity
  • Percentage of Participants With Positive PAL-IgM [ Time Frame: Baseline, Week 24 ]
    Antibody Positivity
  • Percentage of Participants With Positive Anti-PEG-IgM [ Time Frame: Baseline, Week 24 ]
    Antibody positivity
  • Percentage of Participants With Positive Neutralizing Antibodies [Nab] [ Time Frame: Baseline, Week 24 ]
    Antibody positivity
  • Percentage of Participants With Positive Anti-PAL-IgE Antibodies [ Time Frame: Baseline, Week 24 ]
    Antibody positivity
  • Percentage of Participants With Positive Anti-PAL-PEG IgE Antibodies [ Time Frame: Baseline, Week 24 ]
    Antibody positivity
Original Secondary Outcome Measures  ICMJE
 (submitted: March 20, 2012)
  • Safety Assessments [ Time Frame: Minimum Weekly Assessment of Injection Sites, Vital Signs and Adverse Events. Other Safety Assessments will be performed at other intervals (below): ]
    Safety will be assessed through clinical laboratory tests performed monthly (Chemistry, Hematology, Urinalysis, Complements); Physical Exam every other month; Vital Signs and Injection-site Inspection weekly, Pregnancy Test, ECG and chest x-ray at baseline and at completion of the study. Patients will be assessed for adverse events each time they are seen by clinical personnel.
  • Immunogenicity [ Time Frame: Weekly from Week 1 through Week 24 ]
    All patients will be assessed weekly for immunogenicity throughout the 24 weeks of the study through periodic blood tests for antibodies. Antibodies to be assessed: serum anti rAvPAL-PEG antibodies (anti PAL immunoglobulin G [IgG], anti PAL immunoglobulin M [IgM], anti PEG immunoglobulin G [IgG], anti PEG IgM, anti-rAvPAL-PEG neutralizing antibody, anti-rAvPAL-PEG immunoglobulin E [IgE], and clearing antibodies. If patients experience a hypersensitivity reaction additional labs will be tested: serum tryptase level; sedimentation rate; CRP, C3, and C4.
  • Pharmacokinetics [ Time Frame: Weekly from Week 1-24 ]
    All patients will have a weekly pre-dose blood draw for PK throughout the 24 weeks of the study. : When a safe and efficacious dose is identified all subsequent patients will participate in a PK sub-study where additional PK samples will be drawn at 4-12, 16-24, 28-36, 52-60, 96-120 hours post dose during dose titration. PK measures: half-life, AUC, C-max, T-max and through levels pre-dose.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate Subcutaneously Administered rAvPAL-PEG in Patients With Phenylketonuria for 24 Weeks
Official Title  ICMJE A Phase II, Multi-center, Open-label, Dose-finding Study to Evaluate Safety, Efficacy and Tolerability of Subcutaneously (SC) Administered rAvPAL-PEG in Patients With PKU for 24 Weeks
Brief Summary The primary objective of the study is to evaluate the effect of dosing regimens of multiple subcutaneous (SC) doses of rAvPAL-PEG to induce an early and sustained Phe reduction while decreasing the frequency and severity of hypersensitivity reactions in patients with PKU.
Detailed Description The primary rationale for this study is to define an optimal rAvPAL-PEG dose regimen by establishing the therapeutic effect within the shortest time possible time for induction, titration and maintenance phases while reducing the severity and frequency of hypersensitivity reactions that may lead to dose interruptions. It is hypothesized that these goals can be achieved by keeping rAvPAL-PEG doses low when anti-PEG IgM response is predicted to be high and titrating to an efficacious dose once the IgG response to PAL has developed. Further investigation is needed to determine how early and quickly patients can titrate safely to lower blood Phe; therefore, this protocol proposes to assess two Groups using an induction/titration and maintenance schedule with an aim towards establishing the therapeutic effect safety within an optimal period of time.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Phenylketonuria
Intervention  ICMJE Biological: BMN 165 (rAvPAL-PEG)
Subcutaneous injection of rAvPAL-PEG administered from 1 time up to 5 times per week between 2.5mg up to a maximum of 375mg for 24 weeks.
Other Name: Recombinant Anabaena variabilis phenylalanine ammonia lyase
Study Arms  ICMJE Experimental: Group 1
4-8 week induction of rAvPAL-PEG at 2.5 mg, followed by titration to maintenance dose
Intervention: Biological: BMN 165 (rAvPAL-PEG)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 20, 2012)
24
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2015
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. A diagnosis of PKU, with the following:

    • Current blood Phe concentration of ≥ 600 µmol/L at Screening.
    • Average blood Phe concentration of ≥ 600 µmol/L over the past 6 months, using available data.
    • Naïve to prior treatment with rAvPAL-PEG.
  2. Evidence that the patient is a non responder to Kuvan® treatment (ie, 4 weeks of treatment with 20 mg/kg/day of Kuvan, insufficient response per investigator determination, unsuitable for Kuvan® per Investigator determination, and treatment end date ≥ 2 days prior to Day 1 [ie, first dose]). Patients who have had a previous response to Kuvan® treatment but are not currently taking Kuvan® because of noncompliance and have been off treatment for ≥ 4 months prior to Screening are eligible for participation.
  3. Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any research-related procedures. In the case of participants under the age of 18 or participants who have been deemed mentally unable to provide informed consent, a parent or legal guardian may provide written informed consent (and, if required, the patient will provide written assent).
  4. Willing and able to comply with all study procedures.
  5. Between the ages of 16 and 70 years, inclusive.
  6. 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.
  7. Sexually active patients must be willing to use an acceptable method of contraception while participating in the study.
  8. Maintained a stable diet with no significant modifications during the 4 weeks preceding the administration of study drug and willing to continue with the diet while on study so as to avoid potential variability of response due to variations in dietary intake.
  9. In generally good health as evidenced by physical examination, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and electrocardiogram (ECG) at Screening.

Exclusion Criteria:

  1. Use of any investigational product or investigational medical device within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
  2. Use of any medication that is intended to treat PKU, including use of large amino acids, within 2 days prior to the administration of study drug.
  3. 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.
  4. A prior reaction that included systemic symptoms (eg, respiratory or gastrointestinal problems, hypotension, angioedema, anaphylaxis) to a PEG containing product. Patients 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.
  5. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) or to breastfeed at any time during the study.
  6. 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).
  7. Any condition that, in the view of the PI, places the patient at high risk of poor treatment compliance or of not completing the study.
  8. Alanine aminotransferase (ALT) concentration > 2 times the upper limit of normal.
  9. Creatinine > 1.5 times the upper limit of normal.
  10. A positive test for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen and hepatitis C antibody.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 70 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01560286
Other Study ID Numbers  ICMJE 165-205
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party BioMarin Pharmaceutical
Study Sponsor  ICMJE BioMarin Pharmaceutical
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Debra Lounsbury BioMarin Pharmaceutical
PRS Account BioMarin Pharmaceutical
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP