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


- candidate number10595
- NTR NumberNTR3177
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR29-nov-2011
- Secondary IDsEMR700773-003 Merck Serono S.A. – Geneva
- Public TitleA Phase IIIb, Multicentre, Open-Label, Randomized, Controlled Study of the Efficacy, Safety, and Population Pharmacokinetics of Sapropterin Dihydrochloride (KuvanŽ) in Phenylketonuria (PKU) Patients <4 Years Old.
- Scientific TitleA Phase IIIb, Multicentre, Open-Label, Randomized, Controlled Study of the Efficacy, Safety, and Population Pharmacokinetics of Sapropterin Dihydrochloride (KuvanŽ) in Phenylketonuria (PKU) Patients <4 Years Old.
- ACRONYMSPARK (Safety Paediatric efficAcy)
- hypothesisPrimary objectives of this study:
1. Evaluate the efficacy after 26 weeks of KuvanŽ treatment + Phe-restricted diet therapy in increasing dietary Phe tolerance, as compared to dietary therapy alone in <4 year-old infants and children with phenylketonuria (PKU). Phe tolerance will be defined as the amount of dietary Phe (mg/kg/day) ingested while maintaining blood Phe levels within the range of 120-360 μmol/L (defined as ≥120 to < 360 μmol/L);
2. Evaluate the safety after 26 weeks of KuvanŽ treatment in <4 year-old infants and children with PKU;
3. Evaluate BH4 (tetrahydrobiopterin; sapropterin) EMR700773-003 KuvanŽ in PKU Patients <4 Years Old.

Secondary objectives of the study:
1. Evaluate blood Phe levels for all subjects during the 26-week Study Period;
2. Evaluate the effectiveness of KuvanŽ treatment in increasing dietary Phe tolerance, as compared to pre-KuvanŽ treatment during the 26-week Study Period in <4 year-old infants and children with PKU;
3. Assess neurodevelopmental function during KuvanŽ treatment, as compared to dietary treatment alone, during the 26-week Study Period in <4 year-old infants and children with PKU;
4. Assess potential effects on blood pressure during the 26-weeks Study Period and the 3-year Extension Period;
5. Assess potential effects on growth during the 26- weeks Study Period and the 3-year Extension Period;
6. Evaluate long-term safety, neurodevelopmental outcomes, dietary Phe tolerance, and blood Phe levels in the 3-year Extension Period;
7. Investigate in BH4-responsive individuals the predictive value of the phenylalanine hydroxylase (PAH) genotype.
- Healt Condition(s) or Problem(s) studiedPhenylketonuria (PKU) , KUVAN
- Inclusion criteria1. 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);
2. At least two previous blood Phe levels ≥ 400 μmol/L obtained on 2 separate occasions;
3. Previously responded, as assessed by the Investigator, to a BH4 test, if all 3 of the following criteria are satisfied:
A. The BH4 dose was 20 mg/kg/day;
B. The duration of the test was at least for 24 hours, and;
C. Blood Phe levels decreased by at least 30%. NOTE: If a patient has not undergone a BH4 test prior to Screening, such a test must be performed during Screening, and all 3 of the above criteria must be satisfied for the subject to be eligible for entry into this study.
4. Defined level of dietary Phe tolerance consistent with the diagnosis of PKU;
5. Good adherence to dietary treatment, including prescribed dietary Phe restriction and prescribed amounts of Phe-free protein supplements and low- Phe foods;
6. Maintenance of blood Phe levels within the therapeutic target range of 120-360 μmol/L (defined as ≥120 to <360 μmol/L) over a 1-month period prior to Screening, as assessed by the Investigator;
7. 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 criteriaThe exclusion criteria consist of:
1. Use of KuvanŽ, BioptenŽ, or any unregistered preparation of tetrahydrobiopterin within the previous 30 days, unless for the purposes of a BH4 responsiveness test;
2. Previous exposure to KuvanŽ, BioptenŽ, or any unregistered preparation of tetrahydrobiopterin for >30 days;
3. Known hypersensitivity to KuvanŽ or its excipients;
4. Known hypersensitivity to other approved or nonapproved formulations of tetrahydrobiopterin;
5. Previous diagnosis of BH4 deficiency;
6. Current use of methotrexate, trimethoprim, or other dihydrofolate reductase inhibitors;
7. Current use of medications that are known to affect nitric oxide synthesis, metabolism or action;
8. Current use of levodopa;
9. Current use of experimental or unregistered drugs that may affect the study outcomes;
10. Inability to comply with study procedures;
11. Inability to tolerate oral intake;
12. History of organ transplantation;
13. 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;
14. Other significant disease that in the Investigator’s opinion would exclude the subject from the trial;
15. 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.
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlPlacebo
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 3-mei-2011
- planned closingdate
- Target number of participants50
- InterventionsAfter parent(s)/guardian(s) have signed the Independent Ethics Committee (IEC)-approved informed consent form, subjects will be screened for eligibility to enter the study. Eligible study candidates will then report to the clinic on Day 1 of the 26-week Study Period (the first day of dosing with study treatment) and will be randomized 1:1 to receive either:
1. 10 mg/kg/day KuvanŽ + a Phe-restricted diet;
2. Just a Phe-restricted diet.
They will then have their Phe levels checked twice weekly and will have their Phe intake adjusted every two weeks during the 26-week Study Period. Subjects will also return to the clinic on a monthly basis during the 26-week (6-month) Study Period for scheduled assessments, including monitoring of neuromotor and neurodevelopmental status, growth, and safety (via physical examinations and laboratory testing). Subjects will also undergo blood sampling for PopPK analyses during the Study Period on Day 1 and during Weeks 5-12, inclusive.
Subjects who complete the Study Period will then be eligible to enter the Extension Period, during which all subjects will undergo treatment with KuvanŽ, along with a Phe-restricted diet. The Extension Period will be for a duration of 3 years or until KuvanŽ receives regulatory approval for the treatment of <4 year-old PKU infants and children. Subjects will return to the clinic during the Extension Period every 3 months for safety and efficacy monitoring. At the end of the Extension Period, subjects will return to the clinic 4 weeks post-treatment for a standard follow-up visit to monitor safety.
- Primary outcomeDietary Phe tolerance after 26 weeks (6 months) of treatment with KuvanŽ + a Phe-restricted diet, as compared to just a Phe-restricted diet alone.
- Secondary outcome1. Levels of blood Phe during the Study Period;
2. Change from Baseline (prior to enrolment) in dietary Phe tolerance after 26 weeks (6 months) treatment with KuvanŽ + a Phe-restricted diet vs. just a Phe-restricted diet;
3. Blood pressure during the 26-week Study Period and the 3-year Extension Period;
4. Growth parameters (length or height, weight and maximal occipital-frontal head circumference) during the 26-week Study Period and the 3-year Extension Period;
5. Neuromotor developmental milestones and standardized neurodevelopment test results during the 26-week Study Period and the 3-year Extension Period;
6. Safety, including attention to age group-specific safety concerns (see Sections 3.12 and 7.5.1):
A. Nature, incidence and severity of adverse events;
B. Long-term safety for patients enrolled into the Extension Period;
C. Incidence of hypophenylalaninemia (a blood Phe level <120 μmol/L), and;
D. Changes from baseline in vital signs and clinical laboratory parameters.
7. PopPK endpoints will include:
A. CL/f (apparent clearance);
B. V/f (apparent volume of distribution);
C. AUC0-∞ (area under the plasma concentration curve, time 0 to infinity);
D. Cmax (maximum observed plasma concentration);
E. Tmax (time to maximum plasma concentration), and;
F. t1/2 (terminal elimination half-life).
8. PAH genotype.
- TimepointsFollowing Screening, eligible subjects will be randomized 1:1 to receive either:
1. 10 mg/kg/day KuvanŽ + a Phe-restricted diet;
2. Just a Pherestricted diet over a 26-week Study Period.
It is intended that all subjects will maintain blood Phe levels within a range of 120-360 μmol/L (defined as ≥120 to <360 μmol/L) through monitored dietary intake during the 26-week Study Period. If after approximately 4 weeks, a patient’s Phe tolerance has not increased by >20% vs. Baseline, the KuvanŽ dose will be increased in a single step to 20 mg/kg/day. A population pharmacokinetics (PopPK) study is included in the Study Period, with collection of baseline (pre-treatment) blood samples for measurement of endogenous BH4 levels. PopPK samplings will also be obtained during study Weeks 5-12, inclusive.
After completing the Study Period, subjects will be eligible for enrolment in the Extension Period, in which all subjects who continue in the study will receive KuvanŽ treatment + a Phe-restricted diet. For those patients randomized to the Phe-restricted diet alone during the 26-week Study Period, their starting KuvanŽ dose in the Extension Period will be 10 mg/kg/day. A subject’s treatment during the Extension Period will continue for 3 years or until commercial product is approved and becomes available for <4 year-old patients with PKU.
A repeated measures Analysis of Covariance (ANCOVA) will be performed to assess the primary endpoint, the treatment difference on Phe-tolerance between 26 weeks (6 months) of KuvanŽ + a Pherestricted diet vs. 26 weeks (6 months) of Pherestricted dietary therapy alone. A repeated measures ANCOVA model with baseline Phe tolerance and treatment, age group, visit, blood Phe level and treatment by visit interaction effects which has an unstructured covariance pattern will be considered to compare Phe tolerance at the 26-week (6-month visit) for the 2 treatment groups. Baseline Phe tolerance is defined as the Phe tolerance measured before the first dose of KuvanŽ in the 26-week Study Period.
- Trial web siteN/A
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIES Ralf Vis
- CONTACT for SCIENTIFIC QUERIES A.M. Bosch
- Sponsor/Initiator Academic Medical Center (AMC), Amsterdam, Academic Hospital Maastricht (AZM)
- Funding
(Source(s) of Monetary or Material Support)
Merck Serono S.A. – Geneva
- PublicationsThe first publication will be a publication of the results of the analysis of the primary endpoint(s) that will include data from all trial sites. The Investigator will inform the Sponsor in advance about any plans to publish or present data from the trial. Any publications and presentations of the results (abstracts in journals or newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their representatives, will require pre-submission review by the Sponsor. The Sponsor will not suppress or veto publications but maintains the right to delay publication in order to protect intellectual property rights.
- Brief summaryN/A
- Main changes (audit trail)
- RECORD29-nov-2011 - 17-dec-2011


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