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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01376908
First received: June 17, 2011
Last updated: August 13, 2014
Last verified: August 2014
  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 Merck KGaA:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
    Phenylalanine tolerance will be defined as the amount of dietary Phe (milligram per kilogram per day [mg/kg/day]) ingested 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:
  • 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 ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
    Phenylalanine tolerance will be defined as the amount of dietary Phe (mg/kg/day) ingested while maintaining blood Phe levels within the selected therapeutic target range (defined as >=120 to <360 mcmol/L).

  • Number of subjects with adverse events [ Time Frame: Day 1 up to 3-year extension period or until product is commercially approved ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Dietary Phe tolerance [ Time Frame: Every 6-months during 3-year extension period ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Number of subjects with Phenylalanine Hydroxylase (PAH) genotypes [ Time Frame: Day 1 of 6 months (26 weeks) period ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameter: Apparent clearance (CL/f) [ Time Frame: Weeks 5 to 12 during 6 months (26 weeks) period ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameter: Apparent volume of distribution (V/f) [ Time Frame: Weeks 5 to 12 during 6 months (26 weeks) period ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameter: Maximum observed plasma concentration(Cmax) [ Time Frame: Weeks 5 to 12 during 6 months (26 weeks) period ] [ 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 + Phe-restricted diet therapy
Drug: 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.

Phe-restricted diet alone
Subjects will follow a Phe-restricted diet alone
Other: 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.

  Eligibility

Ages Eligible for Study:   up to 4 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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
Research Site
Gent, Belgium
Czech Republic
Research Site
Praha 10, Czech Republic
Germany
Research Site
Berlin, 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
Napoli, 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
Research Site
Istanbul, Turkey
United Kingdom
Research Site
Birmingham, United Kingdom
Research site
London, United Kingdom
Sponsors and Collaborators
Merck KGaA
Investigators
Study Director: Medical Responsible Merck Serono, a division of Merck KGaA, Darmstadt, Germany
  More Information

No publications provided

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01376908     History of Changes
Other Study ID Numbers: EMR 700773-003, 2009-015768-33
Study First Received: June 17, 2011
Last Updated: August 13, 2014
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 Merck KGaA:
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

ClinicalTrials.gov processed this record on October 01, 2014