Clinical trial NCT01376908: Kuvan® in Phenylketonuria Patients Less Than 4 Years Old
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Phenylketonuria
Keywords: Phenylketonuria (PKU)
Kuvan® (Sapropterin)
Phe-restricted diet
Paediatric <4 years old
responders to BH4
Phe tolerance
Lead sponsor: BioMarin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2011-06-20
Enrollment: 56
Sex: ALL
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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:

  1. The BH4 dose was 20 milligram per kilogram per day (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 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
* 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

Primary outcomes:
measure: Dietary Phenylalanine (Phe) Tolerance at Week 26
timeFrame: Week 26
Secondary outcomes:
measure: Mean Blood Phe Levels
timeFrame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26
measure: Change From Baseline in Dietary Phe Tolerance After 26 Weeks
timeFrame: Baseline and at Week 26 (last observation carried-forward [LOCF])
measure: Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation
timeFrame: From the first dose of study drug administration up to 31 days after the last dose of study drug administration
measure: Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS)
timeFrame: Baseline, Weeks 12, 26
measure: Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development
timeFrame: Baseline and Week 26
measure: Growth Parameters Standard Deviation Scores (SDS)
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, and 26
measure: Number of Subjects With Hypophenylalanemia
timeFrame: Week 26
measure: Dietary Phe Tolerance During Extension Period
timeFrame: Every 6 months during 3 year extension period or until product is commercially approved
measure: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, and 26
measure: Number of Samples With Phenylalanine Hydroxylase (PAH) Gene Mutations
timeFrame: Screening (within 42 days prior to Day 1 of the 26-week study period)
measure: Population Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/f)
timeFrame: Weeks 5 to 12
measure: Population PK Parameter: Apparent Volume of Distribution (V/f)
timeFrame: Weeks 5 to 12
measure: Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity])
timeFrame: Weeks 5 to 12
measure: Population PK Parameter: Terminal Elimination Half-life (t1/2)
timeFrame: Weeks 5 to 12
measure: Population PK Parameter: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Up to Week 26
measure: Population PK Parameter: Time to Maximum Plasma Concentration (Tmax)
timeFrame: Up to Week 26
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Research Site
city: Innsbruck
country: Austria
facility: Research site
city: Bruxelles
country: Belgium
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Praha 10
country: Czechia
facility: Research Site
city: Heidelberg
country: Germany
facility: Research site
city: Munich
country: Germany
facility: Research Site
city: Münster
country: Germany
facility: Research Site
city: Reutlingen
country: Germany
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Rome
country: Italy
facility: Research site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Maastricht
country: Netherlands
facility: Research Site
city: Banska Bystrica
country: Slovakia
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Kosice
country: Slovakia
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research site
Study officials:
affiliation: BioMarin Pharmaceutical
name: Ignacio Alvarez, MD
role: STUDY_DIRECTOR
References:
citation: Muntau AC, Burlina A, Eyskens F, Freisinger P, Leuzzi V, Sivri HS, Gramer G, Pazdirkova R, Cleary M, Lotz-Havla AS, Lane P, Alvarez I, Rutsch F. Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at < 4 years of age with phenylketonuria: results of the 3-year extension of the SPARK open-label, multicentre, randomised phase IIIb trial. Orphanet J Rare Dis. 2021 Aug 3;16(1):341. doi: 10.1186/s13023-021-01968-1.
citation: Muntau AC, Burlina A, Eyskens F, Freisinger P, De Laet C, Leuzzi V, Rutsch F, Sivri HS, Vijay S, Bal MO, Gramer G, Pazdirkova R, Cleary M, Lotz-Havla AS, Munafo A, Mould DR, Moreau-Stucker F, Rogoff D. Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial. Orphanet J Rare Dis. 2017 Mar 9;12(1):47. doi: 10.1186/s13023-017-0600-x.