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

Phenylketonuria Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00925054
• Other study ID #: PAL-002
• Status: Completed
• Phase: Phase 2
• Start date: September 2009
• Est. completion date: June 2015

Study information

• Verified date: February 2019
• Source: BioMarin Pharmaceutical
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Phenylketonuria
• Phenylketonurias

Intervention

Drug:
• rAvPAL-PEG 0.001 mg/kg
In Part 1, the planned starting dose levels is 0.001 mg/kg
• rAvPAL-PEG 0.003 mg/kg
In Part 1, the planned starting dose levels is 0.003 mg/kg
• rAvPAL-PEG 0.01 mg/kg
In Part 1, the planned starting dose levels is 0.01 mg/kg
• rAvPAL-PEG 0.03 mg/kg
In Part 1, the planned starting dose levels is 0.03 mg/kg
• rAvPAL-PEG 0.1 mg/kg
In Part 1, the planned starting dose levels is 0.1 mg/kg

Locations

Country	Name	City	State
United States	Akron Children's Hospital	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	The Children's Hospital	Aurora	Colorado
United States	Children's Memorial Hospital	Chicago	Illinois
United States	Emory Universty	Decatur	Georgia
United States	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota
United States	Mount Sinai School of Medicine	New York	New York
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Washington University Center for Applied Research Sciences	Saint Louis	Missouri
United States	University of Utah Hospital	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
BioMarin Pharmaceutical

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Trough Concentration of BMN 165	Plasma concentrations of rAvPAL-PEG (BMN 165)	Baseline, Baseline/pre-dose, Week 7, and Week 16/Day 106
Primary	Blood Phenylalanine Concentrations		Baseline, Week 1/Day 5, Week 7, Week 16/Day 106
Secondary	Study Drug Related Adverse Events		Screening, Weeks 1-22
Secondary	Number of Participants With Positive PAL IgG Antibody	Antibody against PAL (phenylalanine ammonia lyase) measured over time	Baseline, Week 12
Secondary	Number of Participants With Positive PAL IgM Antibody	Antibody positivity over time	Baseline, Week 12
Secondary	Number of Participants With Positive PEG IgM Antibody	Antibody positivity over time	Baseline, Week 16
Secondary	Number of Participants With Positive PEG IgG Antibody	Antibody positivity over time	Baseline, Week 16
Secondary	Percentage of Participants With Positive Neutralizing Antibodies [NAb]	Antibody positivity over time	Baseline, Week 12
Secondary	Percentage of Participants With Positive PAL IgE Antibody	Antibody positivity over time	Baselline, Week 12
Secondary	Percentage of Participants With Positive Anti-PAL-PEG IgE Antibodies	Antibody positivity over time	Baseline, Week 12