Response to Kuvan® in Subjects With Phenylketonuria (PKU) in a 4 Weeks Testing Period (ENDURE)
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ClinicalTrials.gov Identifier: NCT01082328 |
Recruitment Status
:
Completed
First Posted
: March 8, 2010
Results First Posted
: August 1, 2013
Last Update Posted
: February 27, 2014
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Phenylketonuria | Drug: Kuvan® | Phase 4 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 59 participants |
Allocation: | Non-Randomized |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
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 Start Date : | May 2010 |
Actual Primary Completion Date : | May 2012 |
Actual Study Completion Date : | May 2012 |

Arm | Intervention/treatment |
---|---|
Experimental: Kuvan® |
Drug: Kuvan®
Kuvan® (sapropterin dihydrochloride) oral solution 20 milligram per kilogram (mg/kg) will be given once daily for 28 +/- 1 days.
Other Name: Sapropterin dihydrochloride
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- Percentage of Participants With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level [ Time Frame: Baseline up to Day 28 +/- 1 ]Response to treatment was defined as 30 percent reduction from Baseline in blood phenylalanine (Phe) Level during the 28 +/- 1 days.
- Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal [ Time Frame: Baseline up to Day 42 +/- 3 ]An Adverse Event (AE) is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to Baseline during a clinical study with an investigational medicinal product (IMP), regardless of causal relationship and even if no IMP has been administered.
- Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan® [ Time Frame: Baseline up to Day 28 +/- 1 ]Early responders defined as percentage of participants with at least 30 percent reduction in Phe levels within the first seven days of treatment. Late responders defined as percentage of participants with less than 30 percent reduction in Phe levels within first seven days of treatment, but at least 30 percent reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of participants with Phe levels reduction between 10 and 30 percent at any blood measurement within the 28 +/- 1 days of treatment. Non-responders defined as percentage of participants with a Phe level reduction of less than 10 percent within 28 +/- 1 days.
- 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 [ Time Frame: Baseline up to Day 28 +/- 1 ]The Phenylketonuria (PKU) is categorized as per phenotype into classical PKU: (blood Phe levels greater than [>] 1200 micromole per liter [mcmol/l]), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild Hyperphenylalaninaemia (HPA) (blood Phe levels 300 to 600 mcmol/l).
- Percentage of Early-, Late- and Partial-Responders According to Phenotype [ Time Frame: Baseline up to Day 28 +/- 1 ]The PKU is categorized as per phenotype into classical PKU: (blood Phe levels > 1200 mcmol/l), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild HPA (blood Phe levels 300 to 600 mcmol/l). Early responders defined as percentage of participants with at least 30 percent reduction in Phe levels within the first seven days of treatment. Late responders defined as percentage of participants with less than 30 percent reduction in Phe levels within first seven days of treatment, but at least 30 percent reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of participants with Phe levels reduction between 10 and 30 percent at any blood measurement within the 28 +/- 1 days of treatment.
- Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio [ Time Frame: Baseline, Day 28 ]Phenylalanine-to-tyrosine ratio is the best indicator of dopamine availability in PKU. The change in blood phenylalanine-to-tyrosine ratio at Day 28 was calculated as blood phenylalanine-to-tyrosine ratio at Day 28 minus blood phenylalanine-to-tyrosine ratio at Baseline.

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Ages Eligible for Study: | 4 Years and older (Child, Adult, Senior) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01082328
Norway | |
Department of Paediatric Research, Division of Paediatrics, Oslo University Hospital, Rikshospitalet | |
Oslo, Norway |
Study Director: | Medical Responsible | Merck Serono S.A., an affiliate of Merck KGaA, Darmstadt, Germany |
Additional Information:
Publications:
Responsible Party: | Merck KGaA |
ClinicalTrials.gov Identifier: | NCT01082328 History of Changes |
Other Study ID Numbers: |
EMR 700773-503 |
First Posted: | March 8, 2010 Key Record Dates |
Results First Posted: | August 1, 2013 |
Last Update Posted: | February 27, 2014 |
Last Verified: | January 2014 |
Keywords provided by Merck KGaA:
Phenylketonuria (PKU) Hyperphenylalaninemia (HPA) Kuvan® |
Sapropterin dihydrochloride Kuvan responder Tetrahydrobiopterin (BH4) |
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 |