An Open-Label Phase 3 Study of BMN 165 for Adults With PKU Not Previously Treated w/ BMN 165 (Prism301)
|First Received Date ICMJE||March 18, 2013|
|Last Updated Date||January 30, 2017|
|Start Date ICMJE||May 2013|
|Primary Completion Date||November 2015 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||safety and tolerability [ Time Frame: 1 to 36 weeks ]
Assessments and procedures for safety and blood Phe concentration will be performed every 4 weeks throughout this study. Safety will be monitored throughout the study by assessment of vital signs, physical examination, electrocardiograms (ECGs), AEs, concomitant medications, and clinical laboratory tests (chemistry, hematology, and urinalysis).
|Original Primary Outcome Measures ICMJE
||safety and tolerability [ Time Frame: 14 to 36 weeks ]
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
|Change History||Complete list of historical versions of study NCT01819727 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||blood phe concentration [ Time Frame: 1 to 36 weeks ]
Subjects will be assessed for plasma blood Phe concentration at baseline (predose on Day 1), Week 3, Week 4, and every 4 weeks thereafter.
|Original Secondary Outcome Measures ICMJE
||blood phe concentration [ Time Frame: 14 to 36 weeks ]
All patients will be have their plasma Phe assessed at screening, Day 1, Day 15 and then monthly throughout the study.
|Current Other Outcome Measures ICMJE
||Metabolism [ Time Frame: 1 to 36 weeks ]
All patients will complete a 3-day diety diary to be submitted baseline (predose on Day 1), Week 4, and every 4 weeks thereafter. Their dietary intake will be calculated and analyzed through a computer software program, "Metabolic Pro" The diary data will be analyzed by nutritional software for total kcals, protein, phe, tyrosine, and the percentage of DRI provided for protein, phe, tyrosine, vitamins, and minerals will be evaluated on a monthly basis.
|Original Other Outcome Measures ICMJE
||Metabolism [ Time Frame: 14-36 weeks ]
All patients will complete a 3-day diety diary to be submitted monthly. Their dietary intake will be calculated and analyzed through a computer software program, "Metabolic Pro" Blood and urine tests for glucose, calcium, nitrogen and creatinine will be evaluated on a monthly basis.
|Brief Title ICMJE||An Open-Label Phase 3 Study of BMN 165 for Adults With PKU Not Previously Treated w/ BMN 165|
|Official Title ICMJE||A Phase 3, Open-Label, Randomized, Multi-Center Study to Assess the Safety & Tolerability of an Induction, Titration, and Maintenance Dose Regimen of BMN 165 Self Administered by Adults With PKU Not Previously Treated With BMN 165|
|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 patients 18 to 70 years old with hyperphenylalaninemia due to PKU. Study BMN 165-301 is a Phase 3, open-label, randomized study designed to further characterize the safety of BMN 165 during two induction, titration, and maintenance dose regimens in adults with PKU who have not had previous exposure to BMN 165 (naive). Subjects will be randomized (1:1) to titrate up to one of two dose regimens. Other key features of this study are the dose regimens chosen for induction and titration; the study duration; self administration of study drug; and the chosen tertiary objectives.|
Primary and Secondary Outcomes:
The primary objective of the study is the following:
The secondary objective of the study is the following:
The tertiary objectives of the study are the following:
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The incidence of AEs will be summarized by system organ class, preferred term, relationship to study drug, and severity for the subjects who are randomized to the 40 mg/day dose, the 20 mg/day dose, and overall. A by-subject listing will be provided for those subjects who experience an SAE, including death, or experience an AE associated with early withdrawal from the study or study drug. Hypersensitivity AEs and AEs that result in dosing interruption or dose reduction are of interest, and the percentage of subjects who report these AEs will be presented.
Clinical laboratory data will be summarized by the type of laboratory test for the subjects who are randomized to the 40 mg/day dose, the 20 mg /day dose, and overall. Frequency and percentage of subjects who experience abnormal (ie, outside of reference range) and/or clinically significant abnormalities after study drug administration will be presented for each clinical laboratory test. For each clinical laboratory test, descriptive statistics will be provided for baseline and all subsequent post-baseline visits. Changes from baseline to the post-baseline visits will also be provided. Descriptive statistics, including clinically significant changes from baseline, of vital signs, physical examination results, ECG test results, and immunogenicity test results will also be provided in a similar manner. Additionally, antibodies and titers will be summarized at the scheduled time point.
Detailed statistical methods will be provided in the Statistical Analysis Plan (SAP).
The secondary efficacy endpoint is change from baseline to end of study in blood Phe concentration.
Baseline is defined as the average of blood Phe concentrations collected prior to dosing at the Screening Visit and on Day 1.
The primary analysis method for the secondary endpoint will use a repeated measures model, with change from baseline Phe as the dependent variable and dose (40 mg/day or 20 mg/day), study week, and baseline Phe as independent variables.
A responder analysis will be presented as a cumulative distribution function. The percentage of subjects with blood Phe concentration below "X" umol/L at the end of the study will be plotted and summarized for various "X" as a cumulative distribution function for each of the 2 doses and overall.
Detailed statistical methods will be provided in the SAP.
The statistical analysis method for tertiary endpoints (protein intake; the ADHD-RS IV score) will be descriptive. More details regarding the analysis methods for the tertiary endpoints will be provided in the SAP.
Trough plasma concentrations of BMN 165 will be evaluated.
DMC The Data Monitoring Committee (DMC) will act in an advisory capacity to
BioMarin to monitor subject safety and the efficacy of BMN 165 in subjects who participate in Study BMN 165-301 .The DMC responsibilities may include the following:
|Study Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
All subjects receive Study Drug. Subjects will be randomized (1:1) to titrate up to one of two dose regimens: 20 mg/day or 40 mg/day.Eligible subjects will be randomized 1:1 using an IWRS to titrate to one of two dose regimens:
20 mg/day or 40 mg/day. The randomization will be stratified by blood Phe levels of 600 to 900 µmol/L and >900 µmol/ using the last available blood Phe concentration prior to Day 1 of the study.
|Intervention ICMJE||Drug: BMN 165
After informed consent, eligible subjects will be randomized (1:1) to titrate up to one of two dose regimens: 20 mg/day or 40 mg/day. All subjects will initiate IP at a fixed-dose of 2.5 mg/week for 4 weeks (Induction).
After the Induction Period, subjects will enter the Titration Period (Week 5 up to Week 32) where they will increase their weekly BMN 165 dose to a daily dose regimen of 20 mg/day or 40 mg/day. The Titration Period will be individualized to each subject based on a minimum of 6 weeks (the time it takes to reach a dose regimen of 20 mg/day with no dose interruptions) and up to 28 weeks (accounts for dose interruptions due to AEs). Subjects will stop titration once they have achieved either the 20 mg/day or 40 mg/day dose. A maintenance dose will be administered for 4 weeks.
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||December 2016|
|Primary Completion Date||November 2015 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Individuals eligible to participate in this study must meet all of the following criteria:
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
|Ages||18 Years to 70 Years (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01819727|
|Other Study ID Numbers ICMJE||165-301, Prism301|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|Plan to Share Data||No|
|IPD Description||Not Provided|
|Responsible Party||BioMarin Pharmaceutical|
|Study Sponsor ICMJE||BioMarin Pharmaceutical|
|Collaborators ICMJE||Not Provided|
|Information Provided By||BioMarin Pharmaceutical|
|Verification Date||January 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP