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

• ClinicalTrials.gov Identifier: NCT01732471
• Recruitment Status: Completed
• First Posted: November 22, 2012
• Results First Posted: July 28, 2014
• Last Update Posted: July 28, 2014
• Sponsor: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

Tracking Information

• First Submitted Date: November 19, 2012
• First Posted Date: November 22, 2012
• Results First Submitted Date: June 24, 2014
• Results First Posted Date: July 28, 2014
• Last Update Posted Date: July 28, 2014
• Study Start Date: November 2012
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 25, 2014)

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.

• Original Primary Outcome Measures (submitted: November 19, 2012): Response to Kuvan® after 8-day treatment defined as a reduction in blood Phenylalanine levels of greater than or equal to 30 percent as compared to beginning of the test prior to dosing [ Time Frame: Day 8 ]

Current Secondary Outcome Measures (submitted: July 25, 2014)

• 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.

Original Secondary Outcome Measures (submitted: November 19, 2012)

• Percentage change from baseline in blood phenylalanine level after 8-day Kuvan® therapy [ Time Frame: Baseline and Day 8 ]
• Number of adverse events [ Time Frame: Baseline up to Week 11 (+/- 1 Week) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria
• 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Phenylketonuria

Intervention

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

Study Arms

Experimental: Kuvan®

Intervention: Drug: Kuvan®

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 19, 2012): 90
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: October 2013
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT01732471
• Other Study ID Numbers: EMR 700773_510
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Merck KGaA, Darmstadt, Germany
• Study Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Merck KGaA, Darmstadt, Germany
• Verification Date: July 2014