Kuvan® in Phenylketonuria Patients Less Than 4 Years Old (SPARK)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical
ClinicalTrials.gov Identifier:
NCT01376908
First received: June 17, 2011
Last updated: May 24, 2016
Last verified: May 2016
Results First Received: July 31, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Phenylketonuria
Interventions: Drug: Kuvan®
Other: Phenylalanine (Phe)-restricted diet

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Out of 109 subjects screened for the study, 77 pharmacogenetics (PGx) informed consent forms were signed and 73 samples were analyzed which were used as analysis population for outcome measure 11 "Number of samples with phenylalanine hydroxylase (PAH) gene mutations".

Reporting Groups
  Description
Kuvan® + Phe-restricted Diet Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Phe-restricted Diet Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.

Participant Flow:   Overall Study
    Kuvan® + Phe-restricted Diet     Phe-restricted Diet  
STARTED     27     29  
COMPLETED     25     26  
NOT COMPLETED     2     3  
Protocol Violation                 1                 1  
Withdrawal by Subject                 1                 2  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intention-to-treat (ITT) population consisted of all the randomized subjects at the start of the study and were analyzed according to the group allocated.

Reporting Groups
  Description
Kuvan® + Phe-restricted Diet Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Phe-restricted Diet Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Total Total of all reporting groups

Baseline Measures
    Kuvan® + Phe-restricted Diet     Phe-restricted Diet     Total  
Number of Participants  
[units: participants]
  27     29     56  
Age  
[units: months]
Mean (Standard Deviation)
  21.1  (12.3)     21.2  (12.0)     21.2  (12.1)  
Gender  
[units: subjects]
     
Female     11     15     26  
Male     16     14     30  



  Outcome Measures
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1.  Primary:   Dietary Phenylalanine (Phe) Tolerance at Week 26   [ Time Frame: Week 26 ]

2.  Secondary:   Mean Blood Phe Levels   [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26 ]

3.  Secondary:   Change From Baseline in Dietary Phe Tolerance After 26 Weeks   [ Time Frame: Baseline and at Week 26 (last observation carried-forward [LOCF]) ]

4.  Secondary:   Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation   [ Time Frame: From the first dose of study drug administration up to 31 days after the last dose of study drug administration ]

5.  Secondary:   Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS)   [ Time Frame: Baseline, Weeks 12, 26 ]

6.  Secondary:   Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development   [ Time Frame: Baseline and Week 26 ]

7.  Secondary:   Growth Parameters Standard Deviation Scores (SDS)   [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, and 26 ]

8.  Secondary:   Number of Subjects With Hypophenylalanemia   [ Time Frame: Week 26 ]

9.  Secondary:   Dietary Phe Tolerance During Extension Period   [ Time Frame: Every 6 months during 3 year extension period or until product is commercially approved ]

10.  Secondary:   Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)   [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, and 26 ]

11.  Secondary:   Number of Samples With Phenylalanine Hydroxylase (PAH) Gene Mutations   [ Time Frame: Screening (within 42 days prior to Day 1 of the 26-week study period) ]

12.  Secondary:   Population Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/f)   [ Time Frame: Weeks 5 to 12 ]

13.  Secondary:   Population PK Parameter: Apparent Volume of Distribution (V/f)   [ Time Frame: Weeks 5 to 12 ]

14.  Secondary:   Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity])   [ Time Frame: Weeks 5 to 12 ]

15.  Secondary:   Population PK Parameter: Terminal Elimination Half-life (t1/2)   [ Time Frame: Weeks 5 to 12 ]

16.  Secondary:   Population PK Parameter: Maximum Observed Plasma Concentration (Cmax)   [ Time Frame: Up to Week 26 ]

17.  Secondary:   Population PK Parameter: Time to Maximum Plasma Concentration (Tmax)   [ Time Frame: Up to Week 26 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Merck KGaA Communication Center
Organization: Merck Serono, a division of Merck KGaA
phone: +49-6151-72-5200
e-mail: service@merckgroup.com



Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT01376908     History of Changes
Other Study ID Numbers: EMR 700773-003
2009-015768-33 ( EudraCT Number )
Study First Received: June 17, 2011
Results First Received: July 31, 2015
Last Updated: May 24, 2016
Health Authority: Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicinal Products and Health Products
Czech Republic: State Institute for Drug Control
Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Netherlands: Medicines Evaluation Board (MEB)
Portugal: National Pharmacy and Medicines Institute
Slovakia: State Institute for Drug Control
United Kingdom: Medicines and Healthcare Products Regulatory Agency