Response to Kuvan® in Subjects With Phenylketonuria (PKU) in a 4 Weeks Testing Period (ENDURE)

This study has been completed.
Sponsor:
Collaborators:
Merck Serono Norway
Smerud Medical Research International AS
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01082328
First received: March 5, 2010
Last updated: January 26, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Phenylketonuria
Drug: Kuvan®
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Percentage of Participants With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level [ Time Frame: Baseline up to Day 28 +/- 1 ] [ Designated as safety issue: No ]
    Response to treatment was defined as 30 percent reduction from Baseline in blood phenylalanine (Phe) Level during the 28 +/- 1 days.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 59
Study Start Date: May 2010
Study Completion Date: May 2012
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   4 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT01082328

Locations
Norway
Department of Paediatric Research, Division of Paediatrics, Oslo University Hospital, Rikshospitalet
Oslo, Norway
Sponsors and Collaborators
Merck KGaA
Merck Serono Norway
Smerud Medical Research International AS
Investigators
Study Director: Medical Responsible Merck Serono S.A., an affiliate of Merck KGaA, Darmstadt, Germany
  More Information

Additional Information:
Publications:
Scriver CR, Kaufman S. Hyperphenylanaemia: phenylalanine hydroxylase deficiency. In: Beaudet AL, Sly WS, Valle D, editors. Metabolic and molecular bases of inherited disease. New York: McGraw-Hill 2001;1667-709
National Institute of Health. Phenylketonuria (PKU): screening and management. National Institute of Health Consensus Statement 2003;17(3):1-33.

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01082328     History of Changes
Other Study ID Numbers: EMR 700773-503
Study First Received: March 5, 2010
Results First Received: May 31, 2013
Last Updated: January 26, 2014
Health Authority: Norway: Norwegian Medicines Agency
Denmark: Danish Medicines Agency

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

ClinicalTrials.gov processed this record on August 01, 2014