Safety Paediatric efficAcy phaRmacokinetic with Kuvan®

• Register: EUCTR
• Last refreshed on: 22 May 2017
• Main ID: EUCTR2009-015768-33-NL
• Date of registration: 14/02/2011
• Prospective Registration: Yes
• Primary sponsor: Merck Serono S.A. - Geneva
• Public title: Safety Paediatric efficAcy phaRmacokinetic with Kuvan®
• Scientific 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 - SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®)
• Date of first enrolment: 03/05/2011
• Target sample size: 50
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-015768-33
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: diet only Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Communication Center Merck KGaA
• Affiliation: Merck KGaA

• Name: Communication Center Merck KGaA
• Affiliation: Merck KGaA

Key inclusion & exclusion criteria

Inclusion criteria:
1. 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 42 days in the Screening Period).

2. At least two previous blood Phe levels = 400 µmol/L obtained on 2 separate occasions.

3. Previously responded, as assessed by the Investigator, to a BH4 test, if all 3 of the following criteria are satisfied:
a) The BH4 dose was 20 mg/kg/day.
b) The duration of the test was at least for 24 hours.
c) A 30% decrease in blood Phe levels.
NOTE: If a patient has not undergone a BH4 test prior to Screening, such a test must be performed, (Please refer to the note , section 7.1.1 bullet point #7).

4. Defined level of dietary Phe tolerance consistent with the diagnosis of PKU;

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

6. Maintenance of blood Phe levels within the therapeutic target range of 120-360 µmol/L (defined as =120 to < 360 µmol/L) over a 4-month period prior to Screening, as assessed by the Investigator. At least, the last 4 values of phenylalanine (either from venous blood or dry blood spot) should be assessed, out of which 75% should be within the above therapeutic range.

7. 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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 50
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range 0
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
1. Use of Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin within the previous 30 days, unless for the purposes of a BH4 responsiveness test.
2. Previous exposure to Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin for >30 days.
3. Known hypersensitivity to Kuvan® or its excipients.
4. Known hypersensitivity to other approved or non-approved formulations of tetrahydrobiopterin.
5. Previous diagnosis of BH4 deficiency.
6. Current use of methotrexate, trimethoprim, or other dihydrofolate reductase inhibitors.
7. Current use of medications that are known to affect nitric oxide synthesis, metabolism or action.
8. Current use of levodopa.
9. Current use of experimental or unregistered drugs that may affect the study outcomes.
10. Inability to comply with study procedures.
11. Inability to tolerate oral intake.
12. History of organ transplantation.
13. 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.
14. Other significant disease that in the Investigator’s opinion would exclude the subject from the trial.
15. 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.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Phenylketonuria
MedDRA version: 14.1 Level: LLT Classification code 10034873 Term: Phenylketonuria (PKU) System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Trade Name: Kuvan
Product Name: Sapropterin Dihydrochloride
Product Code: NAP
Pharmaceutical Form: Soluble tablet
INN or Proposed INN: SAPROPTERIN
CAS Number: 62989337
Other descriptive name: tetrahydrobiopterin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Primary end point(s): Dietary Phe tolerance after 26 weeks (6 months) of treatment with Kuvan® + a Phe-restricted diet, as compared to just a Phe-restricted diet alone.

Main Objective: 1. Evaluate the efficacy after 26 weeks of Kuvan® treatment + Phe-restricted diet therapy in increasing dietary Phe tolerance, as compared to dietary therapy alone in <4 year-old infants and children with phenylketonuria (PKU). Phe tolerance will be defined as the amount of dietary Phe (mg/kg/day) ingested while maintaining blood Phe levels within the range of 120-360 µmol/L (defined as =120 to < 360 µmol/L).
2. Evaluate the safety after 26 weeks of Kuvan® treatment in <4 year-old infants and children with PKU.
3. Evaluate BH4 (tetrahydrobiopterin; sapropterin) blood levels via scheduled PopPK samplings.

Secondary Objective: 1. Evaluate blood Phe levels for all subjects during the 26-week Study Period.
2. Evaluate the effectiveness of Kuvan® treatment in increasing dietary Phe tolerance, as compared to pre-Kuvan® treatment during the 26-week Study Period in <4 year-old infants and children with PKU.
3. Assess neurodevelopmental function during Kuvan® treatment, as compared to dietary treatment alone, during the 26-week Study Period in <4 year-old infants and children with PKU.
4. Assess potential effects on blood pressure during the 26-weeks Study Period and the 3-year Extension Period.
5. Assess potential effects on growth during the 26-weeks Study Period and the 3-year Extension Period.
6. Evaluate long-term safety, neurodevelopmental outcomes, dietary Phe tolerance, and blood Phe levels in the 3-year Extension Period.
7. Investigate in BH4-responsive individuals the predictive value of the phenylalanine hydroxylase (PAH) genotype.

Timepoint(s) of evaluation of this end point: 26 weeks (6 months)

Secondary Outcome(s)

Secondary end point(s): -Levels of blood Phe during the 26-week Study Period and the 3-year
Extension Period.
-Change from Baseline (prior to enrolment) in dietary Phe tolerance
after 26 weeks (6 months)
-treatment with Kuvan® + a Phe-restricted diet vs. just a Phe-restricted
diet.
-Dietary Phe tolerance during the 3-year Extension Period.
-Blood pressure during the 26-week Study Period and the 3-year
Extension Period.
-Growth parameters (length or height, weight, and maximum occipitalfrontal
head
circumference) during the 26-week Study Period and the 3-year
Extension Period.
-Neuromotor developmental milestones and standardized
neurodevelopment test results during the 26-week Study Period and the
3-year Extension Period.
-Safety, including attention to age group-specific safety concerns:
-Nature, incidence, and severity of adverse events;
-Long-term safety for patients enrolled into the Extension Period.
-Incidence of hypophenylalaninemia (blood Phe <120 µmol/L);
-Changes from baseline in vital signs and clinical laboratory parameters.
Population PK endpoints will include:
-CL/f (apparent clearance);
-V/f (apparent volume of distribution);
-AUC0-8 (area under the plasma concentration curve, time 0 to infinity);
-Cmax (maximum observed plasma concentration);
-Tmax (time to maximum plasma concentration); and
-t1/2 (terminal elimination half-life).
-PAH genotype

Timepoint(s) of evaluation of this end point: At the end of study part (26 weeks) or at the end of the extension period

Secondary ID(s)

2009-015768-33-GB

NCT01376908

EMR700773-003

Source(s) of Monetary Support

Merck Serono S.A. - Geneva