Clinical trial NCT01889862: Phase 3 Study to Evaluate the Efficacy & Safety of Self-Administered Injections of BMN165 by Adults With PKU
Official title: A Four-Part, Phase 3, Randomized, Double-Blind, Placebo- Controlled, Four-Arm, Discontinuation Study to Evaluate the Efficacy and Safety of Subcutaneous Injections of BMN 165 Self-Administered by Adults With Phenylketonuria (PKU)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Phenylketonuria (PKU)
Keywords: PKU
PEG-PAL
Prism
BioMarin
rAvPAL-PEG
BMN165
Lead sponsor: BioMarin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2013-07-01
Enrollment: 215
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The BMN 165 clinical development program has been designed to demonstrate the safety and efficacy of BMN 165 in reducing blood Phe concentrations in adults with PKU.

Detailed description: 165-302 is a Phase 3, 4 Part, Randomized, Double-Blind, Placebo-Controlled, Discontinuation Study to Evaluate the Efficacy and Safety of Self Administered Subcutaneous Injections of BMN 165 by Adults With PKU.

This study is open only to adults who have been exposed to BMN165 in a previous study.

Study BMN 165-302 is a four-Part, Phase 3 study.

* Part 1: Open-label period
* Part 2: A Randomized, double-blind, placebo-controlled period of 8 weeks
* Part 3: Two sub-Parts to Part 3:- Part 3A - BMN 165 administered using vial and syringe during this open label period. Part 3B - BMN 165 administered using prefilled syringe during this open-label period.
* Part 4: A long-term, open-label extension period.

Eligibility criteria: 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, 165-205, or 165-301) prior to screening
* Have had a stable BMN 165 dose regimen for at least 14 days prior to screening
* Are at least 18 y/o and no older than 70 y/o at screening

  * Subjects who are \< 18 y/o and are already enrolled into Study 165-301 under Amendment #1 (10JAN2014) may enroll into this study
* Has identified a person who is \> 18 y/o who has the neurocognitive and linguistic capacities to comprehend and complete the Profile of Mood States (POMS)-Observer rated scale
* Has identified a competent person(s) \> 18 y/o who can observe the subject during study drug administration at certain points in the study

  * 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, a negative pregnancy test at screening and willing to have additional pregnancy tests during the study
* If sexually active, willing to use two acceptable methods of contraception during and for 4 weeks after the study

  * Males post vasectomy for 2 years with no known pregnancies do not need to use any other forms of contraception during the study.
  * 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
* Have neurocognitive and linguistic capacities to comprehend and answer investigator's prompts for the Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) Investigator rated instrument and to complete the POMS-Subject rated scale
* If applicable, maintained stable dose of medication for Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, or other psychiatric disorder ≥8 weeks prior to enrollment and willing to maintain stable dose throughout study unless a change is medically indicated
* General good health, as evidenced by physical examination, clinical laboratory evaluations, and ECG tests at screening

Exclusion Criteria

Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:

* 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
* Have known hypersensitivity to Dextran® or components of Dextran
* Use or planned use of any injectable drugs containing PEG (except for 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
* A history of organ transplantation or taking chronic immunosuppressive therapy
* A history of substance abuse in the past 12 months or current alcohol or drug abuse
* Current participation in the Kuvan registry study (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.
* 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 2x the upper limit of normal
* Creatinine at least 1.5x the upper limit of normal

Primary outcomes:
measure: Change From Baseline in the Blood Plasma Phenylalanine (Phe) Concentration at Part 2
timeFrame: At Part 2 baseline and change from baseline at Part 2 week 8
Secondary outcomes:
measure: Change From Baseline in the Cognitive and Mood Symptoms Measured by ADHD Rating Scale (RS)-IV Inattention Subscale at Part 2
timeFrame: At Part 2 baseline and change from baseline at Part 2 week 8
measure: Change From Baseline in the Blood Plasma Phenylalanine (Phe) Concentration at Part 4
timeFrame: At Part 4 week 57, 105, 161, 209 and 249
measure: Change From Baseline in the Cognitive and Mood Symptoms Measured by PKU POMS TMD at Part 2
timeFrame: At Part 2 baseline and change from baseline at Part 2 week 8
measure: Change From Baseline in the Cognitive and Mood Symptoms Measured by PKU POMS Confusion Subscale at Part 2
timeFrame: At Part 2 baseline and change from baseline at Part 2 week 8
measure: Change From Baseline in the Cognitive and Mood Symptoms Measured by POMS TMD at Part 2
timeFrame: At Part 2 baseline and change from baseline at Part 2 week 8
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego Clinical and Translational Research Institute
state: California
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Gainesville
country: United States
facility: University of Florida Clinical Research Center
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory Universty, Department of Human Genetics, Division of Medical Genetics
state: Georgia
city: Chicago
country: United States
facility: Ann and Robert H Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana CTSI Clinical Research Center
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville, Kosair Charities Pediatric Clinical Research Unit
state: Kentucky
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University Clinical Research Center at the Mott Center
state: Michigan
city: Columbia
country: United States
facility: University of Missouri Health Center
state: Missouri
city: Saint Louis
country: United States
facility: Washington University Center for Applied Research Sciences
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Camden
country: United States
facility: Cooper Health Systems
state: New Jersey
city: Morristown
country: United States
facility: Atlantic Health System - Morristown Medical Center
state: New Jersey
city: Albany
country: United States
facility: Albany Medical Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai Medical Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: St. Christopher's Hospital for Children
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Children's Hospital
state: Tennessee
city: Houston
country: United States
facility: University of Texas Houston Medical School
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Seattle
country: United States
facility: University of Washinton
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: BioMarin Pharmaceutical
name: Clinical Trial Specialist
role: STUDY_DIRECTOR
References:
citation: Bilder DA, Arnold GL, Dimmock D, Grant ML, Janzen D, Longo N, Nguyen-Driver M, Jurecki E, Merilainen M, Amato G, Waisbren S. Improved attention linked to sustained phenylalanine reduction in adults with early-treated phenylketonuria. Am J Med Genet A. 2022 Mar;188(3):768-778. doi: 10.1002/ajmg.a.62574. Epub 2021 Nov 26.