A Phase IIIb, Multicentre, Open-Label, Randomized, Controlled Study of the Efficacy, Safety, and Population Pharmacokinetics of Sapropterin Dihydrochloride (Kuvan®) in Phenylketonuria (PKU) Patients <4 Years Old.

BioMarin Pharmaceutical2 sites in 1 country56 target enrollmentJune 2011

ConditionsPhenylketonuria

InterventionsKuvan®Phenylalanine (Phe)-restricted diet

DrugsKuvan®

Overview

Phase: Phase 3
Intervention: Kuvan®
Conditions: Phenylketonuria
Sponsor: BioMarin Pharmaceutical
Enrollment: 56
Locations: 2
Primary Endpoint: Dietary Phenylalanine (Phe) Tolerance at Week 26
Status: Completed
Last Updated: 8 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

This is a Phase 3b, multicenter, open-label, randomized, controlled study to evaluate efficacy, safety and population pharmacokinetics of sapropterin dihydrochloride (Kuvan®) in less than 4 year-old infants and children with phenylketonuria (PKU).

Registry

clinicaltrials.gov

Start Date

June 2011

End Date

February 17, 2017

Last Updated

8 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

BioMarin Pharmaceutical

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Male or female PKU infants and young children less than (\<) 4 years of age at the scheduled Day 1 visit of the 26-week study period (taking into consideration the maximum of 21 days in the screening period)
•Confirmed clinical and biochemical PKU, including at least two previous blood Phe levels greater than or equal to (\>=) 400 micromol per liter (mcmol/L) obtained on 2 separate occasions
•Previously responded, as assessed by the Investigator, to a tetrahydrobiopterin (BH4) test, if all 3 of the following criteria are satisfied:
•The BH4 dose was 20 milligram per kilogram per day (mg/kg/day)
•The duration of the test was at least for 24 hours
•A 30% decrease in blood Phe levels.
•Defined level of dietary Phe tolerance consistent with the diagnosis of PKU
•Good adherence to dietary treatment, including prescribed dietary Phe restriction and prescribed amounts of Phe-free protein supplements and low-Phe foods
•Maintenance of blood Phe levels within the therapeutic target range of 120-360 mcmol/L (defined as \>=120 to \<360 mcmol/L) over a 4-month period prior to Screening, as assessed by the Investigator
•Parent(s) and/or guardian(s) willing to comply with all study procedures, maintain strict adherence to the diet, and willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study procedures

Exclusion Criteria

•Use of Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin within the previous 30 days, unless for the purposes of a BH4 responsiveness test
•Previous exposure to Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin for greater than (\>)30 days
•Known hypersensitivity to Kuvan® or its excipients
•Known hypersensitivity to other approved or non-approved formulations of tetrahydrobiopterin
•Previous diagnosis of BH4 deficiency
•Current use of methotrexate, trimethoprim, or other dihydrofolate reductase inhibitors
•Current use of medications that are known to affect nitric oxide synthesis, metabolism or action
•Current use of levodopa
•Current use of experimental/other investigational or unregistered drugs that may affect the study outcomes
•Inability to comply with study procedures

Arms & Interventions

Kuvan® + Phe-restricted diet

Subjects will be treated with Kuvan® tablets once daily along with Phe-restricted diet therapy.

Intervention: Kuvan®

Kuvan® + Phe-restricted diet

Subjects will be treated with Kuvan® tablets once daily along with Phe-restricted diet therapy.

Intervention: Phenylalanine (Phe)-restricted diet

Phe-restricted diet alone

Subjects will follow a Phe-restricted diet alone.

Intervention: Phenylalanine (Phe)-restricted diet

Outcomes

Primary Outcomes

Dietary Phenylalanine (Phe) Tolerance at Week 26

Time Frame: Week 26

Phe tolerance was defined as the amount of dietary Phe prescribed (milligram per kilogram per day \[mg/kg/day\]) while maintaining blood Phe levels within the selected therapeutic target range (defined as greater than or equal to \[\>=\] 120 to less than \[\<\] 360 micromoles per liter \[mcmol/L\]).

Secondary Outcomes

Mean Blood Phe Levels(Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26)
Number of Subjects With Hypophenylalanemia(Week 26)
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Baseline, Weeks 4, 8, 12, 16, 20, and 26)
Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity])(Weeks 5 to 12)
Dietary Phe Tolerance During Extension Period(Every 6 months during 3 year extension period or until product is commercially approved)
Population PK Parameter: Maximum Observed Plasma Concentration (Cmax)(Up to Week 26)
Population PK Parameter: Time to Maximum Plasma Concentration (Tmax)(Up to Week 26)
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS)(Baseline, Weeks 12, 26)
Growth Parameters Standard Deviation Scores (SDS)(Baseline, Weeks 4, 8, 12, 16, 20, and 26)
Population PK Parameter: Terminal Elimination Half-life (t1/2)(Weeks 5 to 12)
Change From Baseline in Dietary Phe Tolerance After 26 Weeks(Baseline and at Week 26 (last observation carried-forward [LOCF]))
Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation(From the first dose of study drug administration up to 31 days after the last dose of study drug administration)
Population Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/f)(Weeks 5 to 12)
Population PK Parameter: Apparent Volume of Distribution (V/f)(Weeks 5 to 12)
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development(Baseline and Week 26)
Number of Samples With Phenylalanine Hydroxylase (PAH) Gene Mutations(Screening (within 42 days prior to Day 1 of the 26-week study period))