Clinical trial NCT01082328: Response to Kuvan® in Subjects With Phenylketonuria (PKU) in a 4 Weeks Testing Period
Official title: ENDURE: A Phase IV, Prospective, Open-label, Uncontrolled, Multi-centre Cohort Trial to Assess the Responsiveness of Subjects With Phenylketonuria (PKU) to Treatment With Kuvan® 20 mg/kg/Day for 28 Days
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Phenylketonuria
Keywords: Phenylketonuria (PKU)
Hyperphenylalaninemia (HPA)
Kuvan®
Sapropterin dihydrochloride
Kuvan responder
Tetrahydrobiopterin (BH4)
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
Collaborators: name: Merck Serono Norway
name: Smerud Medical Research International AS
First posted: 2010-03-08
Enrollment: 59
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to evaluate the proportion of responders (that is, greater than or equal to \[\>=\] 30 percent reduction from Baseline in blood phenylalanine \[Phe\] level) to treatment with Kuvan® (sapropterin dihydrochloride) 20 milligram per kilogram per day (mg/kg/day) for 28 days.


Eligibility criteria: Inclusion Criteria:

* Subjects aged 4 years or older at the time the informed consent is obtained
* Subjects diagnosed with PKU (subgroups defined as: classic PKU \[blood Phe greater than {\>}1200 micromole per liter {mcmol/L}\], mild PKU \[blood Phe 600 to1200 mcmol/L\] or mild hyperphenylalaninemia (HPA) \[blood Phe 300 to 600 mcmol/L\]
* Subjects who have received no previous treatment with sapropterin dihydrochloride (either Kuvan® or any other formulations of tetrahydrobiopterin \[BH4\])
* Subjects adherent to their normal diet and willing to adhere to the given diet for the 4 weeks study period
* Subjects who provide a signed (by parent if below 18 years) written informed consent
* Subjects with documented genotyping for both phenylalanine hydroxylase (PAH) mutations (PKU genotype)
* Phenylketonuria (PKU) diagnosis should be documented with at least two historical blood Phe levels above 400 mcmol/L
* Female subjects of childbearing potential (and, if appropriate, male subjects with female partners of childbearing potential) must be willing to avoid pregnancy by using an adequate method of contraception (defined as two barrier methods or one barrier method with spermicide, or intrauterine device or use of the oral female contraceptive) for 4 weeks prior to, during and 12 weeks after the last dose of trial medication
* Women of childbearing potential (for the purpose of this trial, women of childbearing potential are defined as "All female subjects after puberty unless they are post-menopausal for at least 2 years, are surgically sterile or are sexually inactive") must have a negative urine pregnancy test at the Baseline visit

Exclusion Criteria:

* Subjects who have documented BH4 deficiency
* Subjects who have any contraindications to receive Kuvan® as outlined in the summary of product characteristics (SmPC) not willing or able to comply with the study procedures
* Subjects who are pregnant, planning for pregnancy or breastfeeding
* Subjects who have been exposed to any investigational medicinal drugs or treatments within 30 days or 5 half-lives, whichever is longer, prior to the Screening visit
* Subjects using concomitant treatment with folate synthesis inhibiting drugs
* Subjects with concurrent use of Levodopa
* Subjects with concurrent use of inhibitors of dihydrofolate reductase (for example, methotrexate, trimethoprim)
* Subjects with concurrent use of agents that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (for example, glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil
* Subjects who have a concurrent disease potentially interfering safety (for example, seizure disorder, oral steroid dependent asthma, other conditions requiring systemic corticosteroids, or insulin-dependent diabetes mellitus)
* Subjects who have inadequate liver function, defined by alanine aminotransferase (ALT) \>= 2 times upper limit of normal (ULN)
* Subjects who have clinically significant renal dysfunction, defined by serum creatinine \> 250 mcmol/L
* Have any medical condition that, in the judgment of the investigator, would jeopardize the subject's safety following exposure to study drug or would significantly interfere with the subject's ability to comply with the provisions of the protocol

Primary outcomes:
measure: Percentage of Participants With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level
timeFrame: Baseline up to Day 28 +/- 1
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal
timeFrame: Baseline up to Day 42 +/- 3
measure: Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan®
timeFrame: Baseline up to Day 28 +/- 1
measure: Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes
timeFrame: Baseline up to Day 28 +/- 1
measure: Percentage of Early-, Late- and Partial-Responders According to Phenotype
timeFrame: Baseline up to Day 28 +/- 1
measure: Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio
timeFrame: Baseline, Day 28
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Department of Paediatric Research, Division of Paediatrics, Oslo University Hospital, Rikshospitalet
Study officials:
affiliation: Merck Serono S.A., an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
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