Kuvan® in Phenylketonuria Patients Less Than 4 Years Old (SPARK)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical
ClinicalTrials.gov Identifier:
NCT01376908
First received: June 17, 2011
Last updated: May 24, 2016
Last verified: May 2016
  Purpose
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).

Condition Intervention Phase
Phenylketonuria
Drug: Kuvan®
Other: Phenylalanine (Phe)-restricted diet
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by BioMarin Pharmaceutical:

Primary Outcome Measures:
  • Dietary Phenylalanine (Phe) Tolerance at Week 26 [ Time Frame: Week 26 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Mean Blood Phe Levels [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26 ] [ Designated as safety issue: No ]
    Mean blood phe levels were defined as the mean of blood phe levels assessed over each 2-week intervals

  • Change From Baseline in Dietary Phe Tolerance After 26 Weeks [ Time Frame: Baseline and at Week 26 (last observation carried-forward [LOCF]) ] [ Designated as safety issue: No ]
    Phe tolerance was defined as the amount of dietary Phe ingested (mg/kg/day) while maintaining blood Phe levels within the selected therapeutic target range (defined as >=120 to <360 mcmol/L).

  • Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation [ Time Frame: From the first dose of study drug administration up to 31 days after the last dose of study drug administration ] [ Designated as safety issue: Yes ]
    An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study treatment and up to 31 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

  • Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) [ Time Frame: Baseline, Weeks 12, 26 ] [ Designated as safety issue: No ]
    Subjects with normal neuromotor development were assessed by standardized developmental milestones using a parent/guardian report form in the following areas: fine motor, gross motor, language, and personal-social using DDS Test. DDS Test is a widely used to examine the developmental progress of 0-6 years of children. It is a test for screening cognitive & behavioral problems and to assess subjects at risk for developmental problems. The scale reflects what percentage of a certain age group is able to perform a certain task. Tasks are grouped into 4 categories (social contact, fine motor skill, language, and gross motor skill) and include items such as smiles spontaneously, knocks 2 building blocks against each other, speaks 3 words other than "mom" and "dad", or hops on 1 leg. For a newborn, testing can detect neurologic problems. For an infant, testing often serves to reassure parents or to identify the nature of problems early enough hopefu

  • Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development [ Time Frame: Baseline and Week 26 ] [ Designated as safety issue: No ]
    Neurodevelopmental assessments was done using the following age-dependent scales: Bayley III for subjects less than (<) 3.5 years of age and WPPSI III for subjects greater than or equal to (>=) 3.5 to <4 years of age, based on following scores: adaptive behavior composite (ABC) score, cognitive composite (CC) score, language composite (LC) score, motor composite (MC) score., and social-emotional composite (SEC) score. Composite scores ranged from 40 (very poor) to 160 (excellent) and are classified as following: >=115: accelerated performance; 85-114: development within normal limits; 70-84: mildly delayed development; less than or equal to (<=) 69: significant delayed development.

  • Growth Parameters Standard Deviation Scores (SDS) [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, and 26 ] [ Designated as safety issue: No ]
    Growth assessment was performed by monitoring body mass index, height (or length), weight, and maximal occipital-frontal head circumference (MOFHC). Supine length was measured up to 2 years of age thereafter standing height was measured unless subject was unable to stand upright, in which case supine length was measured. Respective parameter SDS was calculated as the value of parameter minus reference mean value of parameter divided by standard deviation of the reference population.

  • Number of Subjects With Hypophenylalanemia [ Time Frame: Week 26 ] [ Designated as safety issue: Yes ]
    Hypophenylalanemia is defined as the condition of blood Phe levels <120 mcmol/L.

  • Dietary Phe Tolerance During Extension Period [ Time Frame: Every 6 months during 3 year extension period or until product is commercially approved ] [ Designated as safety issue: No ]
    Phe tolerance was defined as the amount of dietary Phe ingested (mg/kg/day) while maintaining blood Phe levels within the selected therapeutic target range (defined as >=120 to <360 mcmol/L).

  • Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, and 26 ] [ Designated as safety issue: No ]
  • Number of Samples With Phenylalanine Hydroxylase (PAH) Gene Mutations [ Time Frame: Screening (within 42 days prior to Day 1 of the 26-week study period) ] [ Designated as safety issue: No ]
    The DNA samples received were quantified by using a nanophotometer, and were aliquoted to a concentration of 20 nanogram/microliter DNA and aliquots from each sample were distributed to one 96-well plate. All samples were Sanger sequenced regarding exons 1 to 13 of the PAH gene in forward direction using the DNAs in the 96-well plate. All samples showing variants were Sanger sequenced regarding the concerned exon in reverse direction using DNA from the original tube. All samples showing a homozygous mutation were analyzed by MLPA. All samples showing only 1 mutation were analyzed by MLPA. All samples showing only 1 or no mutation were resequenced completely (exons 1 to 13) in both directions.

  • Population Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/f) [ Time Frame: Weeks 5 to 12 ] [ Designated as safety issue: No ]
    CL/f is the rate at which a drug is removed from the body via renal, hepatic and other clearance pathways.The reason for pooling subjects receiving Kuvan and subjects with Phe-restricted Diet was to facilitate the estimation of baseline endogenous value of BH4 which can only be observed in subjects not receiving the treatment. Ignoring this baseline endogenous value would have led to biased stimated of the Kuvan PK parameters. This pooling assumes that the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 are the same for the 2 arms and so cannot be presented in terms of per arm/per treatment group based as per the planned analysis.

  • Population PK Parameter: Apparent Volume of Distribution (V/f) [ Time Frame: Weeks 5 to 12 ] [ Designated as safety issue: No ]
    V/f is defined as the distribution of a medication between the plasma and the rest of the body after the dose. It is the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of the drug. The reason for pooling subjects receiving Kuvan and subjects with Phe-restricted Diet was to facilitate the estimation of baseline endogenous value of BH4 which can only be observed in subjects not receiving the treatment. Ignoring this baseline endogenous value would have led to biased stimated of the Kuvan PK parameters. This pooling assumes that the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 are the same for the 2 arms and so cannot be presented in terms of per arm/per treatment group based as per the planned analysis.

  • Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity]) [ Time Frame: Weeks 5 to 12 ] [ Designated as safety issue: No ]
    AUC [0-infinity] was estimated by determining total area under the curve of the concentration versus time curve extrapolated to infinity. Since AUC could not be obtained from non-compartmental analysis because of sparse data, AUC = Dose/(CL/F); CL/F was population apparent clearance estimated from the population PK model, & Dose the actual total dose received by the patient on one dosing interval. The reason for pooling subjects receiving Kuvan &subjects with Phe-restricted Diet was to facilitate estimation of baseline endogenous value of BH4 which can only be observed in subjects not receiving treatment. Ignoring this baseline endogenous value would have led to biased estimated of Kuvan PK parameters. This pooling assumes that the the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 were same for the 2 arms and cannot be presented per arm/per treatment group as per planned analysis.

  • Population PK Parameter: Terminal Elimination Half-life (t1/2) [ Time Frame: Weeks 5 to 12 ] [ Designated as safety issue: No ]
    The t1/2 was defined as the time required for plasma concentration of drug to decrease 50 percent (%) in the final stage of elimination. Since t1/2 could not be obtained from non-compartmental analysis because of sparse data, t1/2 was estimated as Log(2)*(V/F)/(CL/F), where V/F & CL/F were the population apparent central Volume & clearance, estimated from population PK model. The reason for pooling subjects receiving Kuvan & subjects with Phe-restricted Diet was to facilitate the estimation of baseline endogenous value of BH4 which can only observed in subjects not receiving treatment. Ignoring this baseline endogenous value would have led biased stimated of the Kuvan PK parameters. This pooling assumes that the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 are the same for the 2 arms and so cannot be presented in terms of per arm/per treatment group based as per the planned analysis.

  • Population PK Parameter: Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Up to Week 26 ] [ Designated as safety issue: No ]
  • Population PK Parameter: Time to Maximum Plasma Concentration (Tmax) [ Time Frame: Up to Week 26 ] [ Designated as safety issue: No ]

Enrollment: 56
Study Start Date: June 2011
Estimated Study Completion Date: February 2017
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Kuvan® + Phe-restricted diet
Subjects will be treated with Kuvan® tablets once daily along with Phe-restricted diet therapy.
Drug: Kuvan®
Kuvan® (sapropterin dihydrochloride) tablets will be administered orally at the dose of 10 mg/kg/day and will 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.
Other Name: Sapropterin dihydrochloride
Other: Phenylalanine (Phe)-restricted diet
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.
Phe-restricted diet alone
Subjects will follow a Phe-restricted diet alone.
Other: Phenylalanine (Phe)-restricted diet
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.

  Eligibility

Ages Eligible for Study:   up to 4 Years   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01376908

Locations
Austria
Research Site
Graz, Austria
Research site
Innsbruck, Austria
Belgium
Research Site
Bruxelles, Belgium
Research Site
Edegem, Belgium
Czech Republic
Research Site
Praha 10, Czech Republic
Germany
Research site
Heidelberg, Germany
Research Site
Munich, Germany
Research Site
Münster, Germany
Research Site
Reutlingen, Germany
Italy
Research Site
Bologna, Italy
Research Site
Milano, Italy
Research Site
Padova, Italy
Research Site
Roma, Italy
Research site
Rome, Italy
Netherlands
Research Site
Amsterdam, Netherlands
Research Site
Maastricht, Netherlands
Slovakia
Research Site
Banska Bystrica, Slovakia
Research Site
Bratislava, Slovakia
Research Site
Kosice, Slovakia
Turkey
Research Site
Ankara, Turkey
United Kingdom
Research Site
Birmingham, United Kingdom
Research site
London, United Kingdom
Sponsors and Collaborators
BioMarin Pharmaceutical
Investigators
Study Director: Medical Responsible Merck Serono, a division of Merck KGaA, Darmstadt, Germany
  More Information

Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT01376908     History of Changes
Other Study ID Numbers: EMR 700773-003  2009-015768-33 
Study First Received: June 17, 2011
Results First Received: July 31, 2015
Last Updated: May 24, 2016
Health Authority: Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicinal Products and Health Products
Czech Republic: State Institute for Drug Control
Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Netherlands: Medicines Evaluation Board (MEB)
Portugal: National Pharmacy and Medicines Institute
Slovakia: State Institute for Drug Control
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by BioMarin Pharmaceutical:
Phenylketonuria (PKU)
Kuvan® (Sapropterin)
Phe-restricted diet
Paediatric <4 years old
responders to BH4
Phe tolerance

Additional relevant MeSH terms:
Phenylketonurias
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Verapamil
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents

ClinicalTrials.gov processed this record on July 28, 2016