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.

• Register: Netherlands Trial Register
• Last refreshed on: 28 April 2013
• Main ID: NTR3177
• Date of registration: 29/11/2011
• Primary sponsor: Academic Medical Center (AMC)
• Public 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.
• 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)
• Date of first enrolment: 3/5/2011
• Target sample size: 50
• Recruitment status: recruiting
• URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3177
• Study type: intervention
• Study design: Randomised: Yes; Masking: None; Control: Placebo; Group: Parallel; Type: 2 or more arms, randomized

Countries of recruitment

The Netherlands

Contacts

• Name: A.M. Bosch

• Name: Ralf Vis

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 21 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, and;

C. Blood Phe levels decreased by at least 30%.
NOTE: If a patient has not undergone a BH4 test prior to Screening, such a test must be performed during Screening, and all 3 of the above criteria must be satisfied for the subject to be eligible for entry into this study.

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 1-month
period prior to Screening, as assessed by the
Investigator;

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.
Exclusion criteria: The exclusion criteria consist of:

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 nonapproved 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:

Health Condition(s) or Problem(s) studied

Phenylketonuria (PKU) , KUVAN

Intervention(s)

After parent(s)/guardian(s) have signed the
Independent Ethics Committee (IEC)-approved
informed consent form, subjects will be screened for eligibility to enter the study. Eligible study candidates will then report to the clinic on Day 1 of the 26-week Study Period (the first day of dosing with study treatment) and will be randomized 1:1 to receive either:

1. 10 mg/kg/day Kuvan® + a Phe-restricted
diet;

2. Just a Phe-restricted diet.

They will then have their Phe levels checked twice weekly and will have their Phe intake adjusted every two weeks during the 26-week Study Period. Subjects will also return to the clinic on a monthly basis during the 26-week (6-month) Study Period for scheduled assessments, including monitoring of neuromotor and neurodevelopmental status, growth, and safety (via physical examinations and laboratory testing). Subjects will also undergo blood sampling for PopPK analyses during the Study Period on Day 1 and during Weeks 5-12, inclusive.

Subjects who complete the Study Period will then be eligible to enter the Extension Period, during which all subjects will undergo treatment with Kuvan®, along with a Phe-restricted diet. The Extension Period will be for a duration of 3 years or until Kuvan® receives regulatory approval for the treatment of <4 year-old PKU infants and children. Subjects will return to the clinic during the Extension Period every 3 months for safety and efficacy monitoring. At the end of the Extension Period, subjects will return to the clinic 4 weeks post-treatment for a standard follow-up visit
to monitor safety.

Primary Outcome(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.

Secondary Outcome(s)

1. Levels of blood Phe during the Study Period;

2. 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;

3. Blood pressure during the 26-week Study Period
and the 3-year Extension Period;

4. Growth parameters (length or height, weight and
maximal occipital-frontal head circumference)
during the 26-week Study Period and the 3-year
Extension Period;

5. Neuromotor developmental milestones and
standardized neurodevelopment test results during
the 26-week Study Period and the 3-year
Extension Period;

6. Safety, including attention to age group-specific
safety concerns (see Sections 3.12 and 7.5.1):

A. Nature, incidence and severity of adverse
events;

B. Long-term safety for patients enrolled into the
Extension Period;

C. Incidence of hypophenylalaninemia (a blood
Phe level <120 μmol/L), and;

D. Changes from baseline in vital signs and
clinical laboratory parameters.

7. PopPK endpoints will include:

A. CL/f (apparent clearance);

B. V/f (apparent volume of distribution);

C. AUC0-∞ (area under the plasma concentration
curve, time 0 to infinity);

D. Cmax (maximum observed plasma
concentration);

E. Tmax (time to maximum plasma
concentration), and;

F. t1/2 (terminal elimination half-life).

8. PAH genotype.

Secondary ID(s)

EMR700773-003

Source(s) of Monetary Support

Merck Serono S.A. ? Geneva

Secondary Sponsor(s)

Academic Hospital Maastricht (AZM)