Overview

This trial is active, not recruiting.

Condition phenylketonuria
Treatments kuvan®, phenylalanine (phe)-restricted diet
Phase phase 3
Sponsor Merck KGaA
Start date June 2011
End date July 2014
Trial size 56 participants
Trial identifier NCT01376908, 2009-015768-33, EMR 700773-003

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).

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Subjects will be treated with Kuvan® tablets once daily + Phe-restricted diet therapy
kuvan®
Kuvan® tablets contain 100 milligram (mg) of sapropterin dihydrochloride. Study Period (26 weeks): Starting Kuvan® dose is 10 mg/kg/day and may be escalated to 20 mg/kg/day if after 4 weeks a subject's Phe tolerance is not increased by at least 20% versus baseline. Phe-restricted diet: Study Period (26 weeks): Phe intake will be adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
(Other)
Subjects will follow a Phe-restricted diet alone
phenylalanine (phe)-restricted diet
During Study Period (26 weeks): Phe intake will be adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.

Primary Outcomes

Measure
Dietary Phe tolerance after 6 months (26 weeks) of treatment with Kuvan® + a Phe -restricted diet versus just a Phe-restricted diet alone
time frame: 6 months (26 weeks)

Secondary Outcomes

Measure
Levels of blood Phe
time frame: Day 1, thereafter every 2 weeks up to 6-month (26 weeks) period and every 3-month up to 3 year extension period or until product is commercially approved
Change from Baseline in dietary Phe tolerance after 26 weeks (6 months) treatment with Kuvan® + a Phe-restricted diet versus just a Phe-restricted diet alone
time frame: Baseline and 6 months (26 weeks)
Number of subjects with adverse events
time frame: Day 1 up to 3-year extension period or until product is commercially approved
Neuromotor developmental milestones assessed by using Denver Developmental Scale
time frame: Day 1, thereafter every 3-month up to 6-month (26 weeks) period and every 6-month up to 3-year extension period or until product is commercially approved
Neurodevelopmental status assessed by using Bayley III Scales of Infant and Toddler Development and Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III)
time frame: Day 1, 6 months (26 weeks) and every 6-month up to 3-year extension period or until product is commercially approved
Linear growth assessments
time frame: Day 1, thereafter every month up to 6-month (26 weeks) period and every 3 month up to 3-year extension period or until product is commercially approved
Body weight assessments
time frame: Day 1, thereafter every month up to 6-month (26 weeks) period and every 3 month up to 3-year extension period or until product is commercially approved
Maximum occipital-frontal head circumference assessments
time frame: Day 1, thereafter every month up to 6-month (26 weeks) period and every 3 month up to 3-year extension period or until product is commercially approved
Number of subjects with hypophenylalaninemia (blood Phe levels less than 120 mcmol/L)
time frame: Day 1 up to 3-year extension period or until product is commercially approved
Dietary Phe tolerance
time frame: Every 6-months during 3-year extension period
Blood pressure assessments
time frame: Day 1 , thereafter every month up to 6-month (26 weeks) period and thereafter every 3-month up to 3-year extension period or until product is commercially approved
Number of subjects with Phenylalanine Hydroxylase (PAH) genotypes
time frame: Day 1 of 6 months (26 weeks) period
Population pharmacokinetic parameter: Apparent clearance (CL/f)
time frame: Weeks 5 to 12 during 6 months (26 weeks) period
Population pharmacokinetic parameter: Apparent volume of distribution (V/f)
time frame: Weeks 5 to 12 during 6 months (26 weeks) period
Population pharmacokinetic parameter: Area under the plasma concentration curve, time 0 to infinity (AUC [0-infinity])
time frame: Weeks 5 to 12 during 6 months (26 weeks) period
Population pharmacokinetic parameter: Time to maximum plasma concentration (Tmax) and terminal elimination half-life (t1/2)
time frame: Weeks 5 to 12 during 6 months (26 weeks) period
Population pharmacokinetic parameter: Maximum observed plasma concentration(Cmax)
time frame: Weeks 5 to 12 during 6 months (26 weeks) period

Eligibility Criteria

Male or female participants up to 4 years old.

Inclusion Criteria: - Male or female PKU infants and young children <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 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: 1. The BH4 dose was 20 mg/kg/day 2. The duration of the test was at least for 24 hours 3. 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 1-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 - Inability to tolerate oral intake - History of organ transplantation - Concurrent disease or condition that would interfere with study participation or increase the risk for adverse events, including seizure disorders, corticosteroid administration, active malignancy, diabetes mellitus, severe congenital heart disease, renal or hepatic failure - Other significant disease that in the Investigator's opinion would exclude the subject from the trial - Any condition that, in the view of the Principal Investigator renders the subject at high risk for failure to comply with treatment or to complete the study

Additional Information

Official title 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.
Trial information was received from ClinicalTrials.gov and was last updated in August 2014.
Information provided to ClinicalTrials.gov by Merck KGaA.