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

January 26, 2014 updated by: Merck KGaA, Darmstadt, Germany

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

59

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Norway
      • Oslo, Norway
        • Department of Paediatric Research, Division of Paediatrics, Oslo University Hospital, Rikshospitalet

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • Sapropterin dihydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline up to Day 28 +/- 1

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline up to Day 42 +/- 3
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.
Baseline up to Day 28 +/- 1
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).
Baseline up to Day 28 +/- 1
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.
Baseline up to Day 28 +/- 1
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.
Baseline, Day 28

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Merck KGaA, Darmstadt, Germany

Collaborators

Smerud Medical Research International AS
Merck Serono Norway

Investigators

  • Study Director: Medical Responsible, Merck Serono S.A., an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2010

Primary Completion (Actual)

May 1, 2012

Study Completion (Actual)

May 1, 2012

Study Registration Dates

First Submitted

March 5, 2010

First Submitted That Met QC Criteria

March 5, 2010

First Posted (Estimate)

March 8, 2010

Study Record Updates

Last Update Posted (Estimate)

February 27, 2014

Last Update Submitted That Met QC Criteria

January 26, 2014

Last Verified

January 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EMR 700773-503

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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