Kuvan® in Phenylketonuria Patients Less Than 4 Years Old

Phenylketonuria Clinical Trial

— SPARK  

Official title:

A Phase IIIb, Multicentre, Open-Label, Randomized, Controlled Study of the Efficacy, Safety, and Population Pharmacokinetics of Sapropterin Dihydrochloride (Kuvan®) in Phenylketonuria (PKU) Patients <4 Years Old.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01376908
• Other study ID #: EMR 700773-003
• Secondary ID: 2009-015768-33
• Status: Active, not recruiting
• Phase: Phase 3
• First received: June 17, 2011
• Last updated: August 13, 2014
• Start date: June 2011
• Est. completion date: February 2017

Study information

• Verified date: August 2014
• Source: Merck KGaA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Federal Office for Safety in Health CareBelgium: Federal Agency for Medicinal Products and Health ProductsCzech Republic: State Institute for Drug ControlGermany: Federal Institute for Drugs and Medical DevicesItaly: The Italian Medicines AgencyNetherlands: Medicines Evaluation Board (MEB)Portugal: National Pharmacy and Medicines InstituteSlovakia: State Institute for Drug ControlUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

This is a Phase 3b, multicenter, open-label, randomized, controlled study to evaluate efficacy, safety and population pharmacokinetics of sapropterin dihydrochloride (Kuvan®) in less than 4 year-old infants and children with Phenylketonuria (PKU).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 56
• Est. completion date: February 2017
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 4 Years

Eligibility

Inclusion Criteria:

• Male or female PKU infants and young children <4 years of age at the scheduled Day 1 visit of the 26-week Study Period (taking into consideration the maximum of 21 days in the Screening Period)

• Confirmed clinical and biochemical PKU, including at least two previous blood Phe levels greater than or equal to (>=) 400 mcmol/L obtained on 2 separate occasions

• Previously responded, as assessed by the Investigator, to a tetrahydrobiopterin (BH4) test, if all 3 of the following criteria are satisfied:

1. The BH4 dose was 20 mg/kg/day

2. The duration of the test was at least for 24 hours

3. A 30% decrease in blood Phe levels.

• Defined level of dietary Phe tolerance consistent with the diagnosis of PKU

• Good adherence to dietary treatment, including prescribed dietary Phe restriction and prescribed amounts of Phe-free protein supplements and low-Phe foods

• Maintenance of blood Phe levels within the therapeutic target range of 120-360 mcmol/L (defined as >=120 to <360 mcmol/L) over a 1-month period prior to Screening, as assessed by the Investigator

• Parent(s) and/or guardian(s) willing to comply with all study procedures, maintain strict adherence to the diet, and willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study procedures

Exclusion Criteria:

• Use of Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin within the previous 30 days, unless for the purposes of a BH4 responsiveness test

• Previous exposure to Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin for greater than (>)30 days

• Known hypersensitivity to Kuvan® or its excipients

• Known hypersensitivity to other approved or non-approved formulations of tetrahydrobiopterin

• Previous diagnosis of BH4 deficiency

• Current use of methotrexate, trimethoprim, or other dihydrofolate reductase inhibitors

• Current use of medications that are known to affect nitric oxide synthesis, metabolism or action

• Current use of levodopa

• Current use of experimental/other investigational or unregistered drugs that may affect the study outcomes

• Inability to comply with study procedures

• Inability to tolerate oral intake

• History of organ transplantation

• Concurrent disease or condition that would interfere with study participation or increase the risk for adverse events, including seizure disorders, corticosteroid administration, active malignancy, diabetes mellitus, severe congenital heart disease, renal or hepatic failure

• Other significant disease that in the Investigator's opinion would exclude the subject from the trial

• Any condition 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Phenylketonuria
• Phenylketonurias

Intervention

Drug:
• Kuvan®
Kuvan® tablets contain 100 milligram (mg) of sapropterin dihydrochloride. Study Period (26 weeks): Starting Kuvan® dose is 10 mg/kg/day and may be escalated to 20 mg/kg/day if after 4 weeks a subject's Phe tolerance is not increased by at least 20% versus baseline. Phe-restricted diet: Study Period (26 weeks): Phe intake will be adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.

Other:
• Phenylalanine (Phe)-restricted diet
During Study Period (26 weeks): Phe intake will be adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.

Locations

Country	Name	City	State
Austria	Research Site	Graz
Austria	Research site	Innsbruck
Belgium	Research Site	Bruxelles
Belgium	Research Site	Edegem
Belgium	Research Site	Gent
Czech Republic	Research Site	Praha 10
Germany	Research Site	Berlin
Germany	Research site	Heidelberg
Germany	Research Site	Munich
Germany	Research Site	Münster
Germany	Research Site	Reutlingen
Italy	Research Site	Bologna
Italy	Research Site	Milano
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Roma
Italy	Research site	Rome
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Maastricht
Slovakia	Research Site	Banska Bystrica
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Kosice
Turkey	Research Site	Ankara
Turkey	Research Site	Istanbul
United Kingdom	Research Site	Birmingham
United Kingdom	Research site	London

Sponsors (1)

Lead Sponsor	Collaborator
Merck KGaA

Countries where clinical trial is conducted

Austria,  Belgium,  Czech Republic,  Germany,  Italy,  Netherlands,  Slovakia,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dietary Phe tolerance after 6 months (26 weeks) of treatment with Kuvan® + a Phe -restricted diet versus just a Phe-restricted diet alone	Phenylalanine tolerance will be defined as the amount of dietary Phe (milligram per kilogram per day [mg/kg/day]) ingested while maintaining blood Phe levels within the selected therapeutic target range (defined as greater than or equal to (>=) 120 to less than (<) 360 micromoles per liter [mcmol/L]).	6 months (26 weeks)	No
Secondary	Levels of blood Phe		Day 1, thereafter every 2 weeks up to 6-month (26 weeks) period and every 3-month up to 3 year extension period or until product is commercially approved	No
Secondary	Change from Baseline in dietary Phe tolerance after 26 weeks (6 months) treatment with Kuvan® + a Phe-restricted diet versus just a Phe-restricted diet alone	Phenylalanine tolerance will be defined as the amount of dietary Phe (mg/kg/day) ingested while maintaining blood Phe levels within the selected therapeutic target range (defined as >=120 to <360 mcmol/L).	Baseline and 6 months (26 weeks)	No
Secondary	Number of subjects with adverse events		Day 1 up to 3-year extension period or until product is commercially approved	Yes
Secondary	Neuromotor developmental milestones assessed by using Denver Developmental Scale		Day 1, thereafter every 3-month up to 6-month (26 weeks) period and every 6-month up to 3-year extension period or until product is commercially approved	No
Secondary	Neurodevelopmental status assessed by using Bayley III Scales of Infant and Toddler Development and Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III)		Day 1, 6 months (26 weeks) and every 6-month up to 3-year extension period or until product is commercially approved	No
Secondary	Linear growth assessments		Day 1, thereafter every month up to 6-month (26 weeks) period and every 3 month up to 3-year extension period or until product is commercially approved	No
Secondary	Body weight assessments		Day 1, thereafter every month up to 6-month (26 weeks) period and every 3 month up to 3-year extension period or until product is commercially approved	No
Secondary	Maximum occipital-frontal head circumference assessments		Day 1, thereafter every month up to 6-month (26 weeks) period and every 3 month up to 3-year extension period or until product is commercially approved	No
Secondary	Number of subjects with hypophenylalaninemia (blood Phe levels less than 120 mcmol/L)		Day 1 up to 3-year extension period or until product is commercially approved	Yes
Secondary	Dietary Phe tolerance		Every 6-months during 3-year extension period	No
Secondary	Blood pressure assessments		Day 1 , thereafter every month up to 6-month (26 weeks) period and thereafter every 3-month up to 3-year extension period or until product is commercially approved	No
Secondary	Number of subjects with Phenylalanine Hydroxylase (PAH) genotypes		Day 1 of 6 months (26 weeks) period	No
Secondary	Population pharmacokinetic parameter: Apparent clearance (CL/f)		Weeks 5 to 12 during 6 months (26 weeks) period	No
Secondary	Population pharmacokinetic parameter: Apparent volume of distribution (V/f)		Weeks 5 to 12 during 6 months (26 weeks) period	No
Secondary	Population pharmacokinetic parameter: Area under the plasma concentration curve, time 0 to infinity (AUC [0-infinity])		Weeks 5 to 12 during 6 months (26 weeks) period	No
Secondary	Population pharmacokinetic parameter: Time to maximum plasma concentration (Tmax) and terminal elimination half-life (t1/2)		Weeks 5 to 12 during 6 months (26 weeks) period	No
Secondary	Population pharmacokinetic parameter: Maximum observed plasma concentration(Cmax)		Weeks 5 to 12 during 6 months (26 weeks) period	No