165-302

Overview

Status: Recruiting
Keywords: PKU , PEG-PAL
IRB Number: 00066308
Specialty: Pediatric Genetics
Sub Specialties: Medical Genetics

Brief Summary

Study BMN 165-302 is a four-part, Phase 3 study enrolling approximately 250 adults (18 to ≤70 years old) with PKU previously treated with BMN 165. Subjects who have completed a prior BMN 165 study (PAL-003 or 165-301) before screening may be eligible for study participation.
 
Part 1 is an open-label period designed to establish eligibility for entry into Part 2 of the study. Subjects who achieve a mean blood Phe reduction of ≥20% (based on a mean of two consecutive assessments) from baseline levels in Study 165-301 are eligible to participate in Part 2. This Part 2 eligibility criterion has been added to better identify a study population in which the treatment effect of BMN 165 can more readily be detected during the randomized, discontinuation portion of the study.
 
Part 2 is a randomized, double-blind, placebo-controlled, four-arm, discontinuation period designed to compare blood Phe levels in subjects treated with BMN 165 and those treated with placebo. The Part 2 expectation is that BMN 165 maintains previously achieved blood Phe reduction in a double-blind, placebo-controlled setting, confirming its Phe-lowering effect in previous, open-label studies. Among placebo-treated subjects, BMN 165 withdrawal is expected to result in rapid and substantial blood Phe increase. Thus, randomized discontinuation is an efficient assessment of treatment effect.
 
In Part 3, subjects perform pharmacokinetic (PK)/pharmacodynamic (PD) blood sampling and subsequent analysis before the long-term extension period (Part 4) to enable assessment of the multiple-dose, exposure-response relationships for safety and efficacy for Part 2 and Part 3. Subsequent sampling and analysis in Part 3 will enable the estimation of PK/PD parameters, assessment of PK comparability between vial and syringe and prefilled syringe BMN 165 drug products, and evaluation of the potential influence of subject factors (eg., age, weight, sex, and antibodies) on BMN 165 PK/ PD.
 
Part 4 is an open-label extension designed to evaluate long-term efficacy and safety and to provide long-term access to BMN 165. Subjects will transition to Part 4 upon completion of Part 3 or if they are not eligible for participation in Part 1 or Part 2.
 
OBJECTIVES:
PART 1: Open-Label Blood Phe Assessment
The objective of Part 1 is to screen subjects for eligibility for entry into for Part 2 of the study and to characterize the safety of BMN 165 (20 or 40 mg/day) in previously exposed subjects who self administer BMN 165.

PART 2: Randomized, Double-Blind Discontinuation
The primary efficacy objective of Part 2 is to evaluate blood Phe concentration in previously exposed subjects who self administer BMN 165 (20 or 40 mg/day) compared with previously exposed subjects who self administer matching placebo.
The secondary efficacy objective of Part 2 is to evaluate inattention and mood symptoms in subjects who self administer BMN 165 (20 or 40 mg/day) compared with previously exposed subjects who self administer matching placebo.
The safety objective of Part 2 is to evaluate the safety of BMN 165 in previously exposed subjects who self administer BMN 165 (20 or 40 mg/day) compared with previously exposed subjects who self administer matching placebo.
The tertiary objectives of Part 2 are the following:
• To characterize dietary protein intake from medical food and intact food in subjects who self administer BMN 165 (20 or 40 mg/day) and those who self administer matching placebo
• To evaluate trough plasma BMN 165 concentration in subjects who self administer BMN 165 (20 or 40 mg/day)
• To characterize immunogenicity in subjects who self administer BMN 165 (20 or 40 mg/day) and those who self administer placebo
• To evaluate hyperactivity symptoms in subjects who self administer BMN 165 (20 or40 mg/day) compared with previously exposed subjects who self administer matching placebo

PART 3: Pharmacokinetic/Pharmacodynamic Assessment
The objectives of Part 3 of this study are as follows:
• To evaluate multiple-dose PK/PD in subjects who self administer BMN 165
• To evaluate PK comparability between BMN 165 vial and syringe drug product and prefilled syringe drug product

PART 4: Long-Term, Open-Label Extension
The objectives of Part 4 of this study are the following:
• To evaluate the long-term effect of multiple dose levels of BMN 165 on blood Phe concentration in subjects who self administer BMN 165 using prefilled syringe
• To characterize long-term inattention, hyperactivity, and mood symptoms in subjects who self administer BMN 165
• To evaluate long-term safety of multiple dose levels of BMN 165 in subjects who self administer BMN 165 using prefilled syringe
• To characterize dietary protein intake from medical food and from intact food in subjects who self administer BMN 165
• To characterize the long-term immunogenicity profile of BMN 165 in subjects who self-administer BMN 165 using prefilled syringe

Principal Investigator: Nicola Longo
Department: Pediatric Genetics
Co Investigator: Nicola Longo
Co Investigator: Sharon Ernst
Co Investigator: Krista Viau
Co Investigator: Chelsey Clegg
Co Investigator: Lorenzo Botto

Contact Information

Name:Carrie Bailey
Phone: 8015873605
Email: carrie.bailey@hsc.utah.edu

Inclusion Criteria

Individuals eligible to participate in this study must meet all of the following criteria:
• Have completed a prior BMN 165 study (PAL-003 or 165-301) prior to screening
• Have had a stable BMN 165 dose for at least 14 days prior to screening
• Are at least 18 years of age and no older than 70 years of age at the time of screening
o Subjects who are <18 years old and are already enrolled into Study 165-301 under Amendment #1  (10JAN2014) may enroll into this study.
• Has identified a person who is ≥ 18 years of age who has the neurocognitive and linguistic capacities to comprehend and complete the POMS-Observer rated scale.
• Has identified a competent person or persons who are ≥ 18 years of age who can observe the subject during study drug administration and for a minimum of 1 hour following administration during Part 3, Week 1; Part 4, Week1; if needed upon return to dosing after an AE; if dosing is increased during Part 4; and per investigator determination.
o A home healthcare nurse may perform the study drug observations.
• Are 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; for minors, parent or guardian provides written consent and assent may be requested
• Are willing and able to comply with all study procedures
• For females of childbearing potential, must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study. (Females are considered not of childbearing potential if they have been in menopause for at least 2 years, have had a tubal ligation at least 1 year prior to screening, or have had a total hysterectomy.)
• If sexually active, must be willing to use two acceptable methods of contraception while participating in the study and 4 weeks after the study
o Males post vasectomy for 2 years with no known pregnancies do not need to use any other forms of contraception during the study.
o Females who have been in menopause for at least 2 years, have had a tubal ligation at least 1 year prior to screening, or have had a total hysterectomy do not need to use any other forms of contraception during the study.
• Have received documented approval from a study dietitian confirming that the subject is capable of maintaining their diet in accordance with dietary information presented in the protocol.
• Have neurocognitive and linguistic capacities to comprehend and answer investigator’s
prompts for the ADHD RS–Investigator rated instrument and to complete the POMS-Subject rated scale
• If applicable, maintained stable dose of medication for ADHD, depression, anxiety, or other psychiatric disorder for ≥8 weeks prior to enrollment and willing to maintain stable dose throughout study unless a change is medically indicated
• Are in generally good health, as evidenced by physical examination, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and ECG tests performed at screening

Exclusion Criteria

Use of any investigational product (except BMN 165) 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 (except BMN 165) intended to treat PKU, including the use of large neutral amino acids, within 2 days prior to the administration of study drug (Day 1, first dose of  BMN 165)
• Have known hypersensitivity to Dextran® or components of Dextran
• Use or planned use of any injectable drugs containing PEG (other than BMN 165), including medroxyprogesterone injection, within 3 months prior to screening and during study participation
• Current use of levodopa
• A positive test for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody (subjects without screens during previous BMN 165 study)
• A history of organ transplantation or on chronic immunosuppressive therapy
• A history of substance abuse (as defined by the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders [DSM]) in the past 12 months or current alcohol or drug abuse
• Current participation in the Kuvan® registry study (PKU Demographics, Outcomes and Safety [PKUDOS]). Patients may discontinue the PKUDOS registry trial to allow enrollment in this study
• Pregnant or breastfeeding at screening or planning to become pregnant (self or partner) or 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)
• Major surgery planned during the study period 
• Any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or terminating early from the study
• Alanine aminotransferase (ALT) concentration at least 2 times the upper limit of normal.
• Creatinine at least 1.5 times the upper limit of normal