A Study to Evaluate Subcutaneously Administered rAvPAL-PEG in Patients With Phenylketonuria for 24 Weeks
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.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Phenylalanine reduction [ Time Frame: Weekly Plasma Phe from Weeks 1-24 ] [ Designated as safety issue: Yes ]All patients will be have their plasma Phe assessed weekly from Week 1 through Week 24 of the study.
- 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): ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: No ]All patients will have a weekly pre-dose blood draw for PK throughout the 24 weeks of the study to measure trough levels.
- Pharmacokinetics Sub-Study [ Time Frame: 4-12, 16-24, 28-36, 52-60, 96-120 hours post dose during dose titration. ] [ Designated as safety issue: No ]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 sub-study measures: half-life, AUC, C-max and T-max.
|Study Start Date:||May 2012|
|Estimated Study Completion Date:||August 2013|
|Estimated Primary Completion Date:||August 2013 (Final data collection date for primary outcome measure)|
Experimental: Open Label
All patients will receive open label study drug
Subcutaneous injection 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
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.
|United States, Colorado|
|The Children's Hospital|
|Aurora, Colorado, United States, 80045|
|United States, Florida|
|University of Florida|
|Gainesville, Florida, United States, 32610|
|United States, Massachusetts|
|Children's Hospital Boston|
|Boston, Massachusetts, United States, 02115|
|United States, Nebraska|
|Nebraska Medical Center|
|Omaha, Nebraska, United States, 68198|
|United States, New York|
|Albany Medical College|
|Albany, New York, United States, 12208|
|United States, Utah|
|Salt Lake City, Utah, United States, 84132|
|Study Director:||Mamuka Mamaladze, MD||BioMarin Pharmaceutical|