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Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria

This study has been completed.
Information provided by (Responsible Party):
Merck KGaA Identifier:
First received: November 19, 2012
Last updated: July 25, 2014
Last verified: July 2014
This is an open-label, non-comparative, Phase 3 study to evaluate the degree, frequency of response and safety of Kuvan® (sapropterin dihydrochloride) in subjects aged 4 to 18 years who have phenylketonuria and with elevated blood phenylalanine level of greater than or equal to 450 micromole per liter.

Condition Intervention Phase
Drug: Kuvan®
Phase 3

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Non-comparative Open-label Clinical Study to Evaluate the Response to and Safety of Kuvan (Sapropterin Dihydrochloride) After 6 Weeks of Treatment in Patients of 4 to 18 Years of Age With Phenylketonuria Who Have Elevated Blood Phenylalanine Levels

Resource links provided by NLM:

Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment [ Time Frame: Day 8 ]
    Response to Kuvan® (sapropterin dihydrochloride) treatment was defined as a reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.

Secondary Outcome Measures:
  • Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Overall Population [ Time Frame: Baseline, Day 8 ]
    Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.

  • Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Sub-population of Responders [ Time Frame: Baseline, Day 8 ]
    Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.

  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population [ Time Frame: Baseline up to Week 11 ]
    An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.

Enrollment: 90
Study Start Date: November 2012
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Kuvan® Drug: Kuvan®
Kuvan® (sapropterin dihydrochloride) will be administered orally at a dose of 20 milligram per kilogram per day (mg/kg/day) once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment will be continued at the same dose for further 6 weeks.
Other Names:
  • Sapropterin dihydrochloride
  • 6R-BH4 tetrahydrobiopterin


Ages Eligible for Study:   4 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Willing and able to provide written informed consent (for children under 18 years old the parent[s]/guardians give informed consent, subjects 14-17 years old give additionally their own written informed consent)
  • Age of 4 - 18 years, inclusive
  • Confirmed clinical and biochemical hyperphenylalaninemia due to phenylketonuria documented by past medical history with at least 2 blood phenylalanine level greater than or equal to 400 micromole per liter obtained in 2 separate occasions
  • Blood phenylalanine level at screening greater than or equal to 450 micromole per liter (mean of two measurements)
  • For women of childbearing potential, a negative urine pregnancy test is required at screening and willingness to use a highly effective method of contraception is required while participating in the study
  • Subject and/or the parent/guardian willing and able to comply with study procedures
  • Subject and/or the parent/guardian willing to continue current diet unchanged during the 8 days response test and to adapt the diet according to phenylalanine therapeutic target range during the 6 week treatment period

Exclusion Criteria:

  • Subject already assessed for responsiveness to sapropterin dihydrochloride or other tetrahydrobiopterin (BH4)
  • Used any investigational agent other than Kuvan® (sapropterin dihydrochloride) within 30 days of screening, or required any investigational agent or vaccine prior to completion of all scheduled study assessments
  • Pregnant or breastfeeding, or considering pregnancy
  • Concurrent disease or conditions that would interfere with study participation or safety (for example, seizure disorder, asthma or other condition requiring oral or parenteral corticosteroid administration, insulin-dependent diabetes, or organ transplantation recipient)
  • Concurrent use of required concomitant treatment with any drug known to inhibit folate synthesis (for example, methotrexate), levodopa, phosphodiesterase type-5 (PDE-5) inhibitors (such as, sildenafil, vardenafil or tadalafil), medications that are known to affect nitric oxide synthesis metabolism or action
  • Any conditions, 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
  • Clinical diagnosis of primary BH4 deficiency
  • Known hypersensitivity to Kuvan® (sapropterin dihydrochloride) or its excipients or to other approved or non-approved formulation of tetrabiopterin
  Contacts and Locations
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Please refer to this study by its identifier: NCT01732471

Please contact Merck KGaA Communication Center
Darmstadt, Germany
Sponsors and Collaborators
Merck KGaA
  More Information

Responsible Party: Merck KGaA Identifier: NCT01732471     History of Changes
Other Study ID Numbers: EMR 700773_510
Study First Received: November 19, 2012
Results First Received: June 24, 2014
Last Updated: July 25, 2014

Keywords provided by Merck KGaA:
EMR 700733_510, Genetic disorder, Phenylketonuria, phenylalanine, Kuvan, sapropterin dihydrochloride

Additional relevant MeSH terms:
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
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents processed this record on May 22, 2017