Primary objectives of this study: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
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Phenylketonuria (PKU)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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
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):
* Nature, incidence and severity of adverse events;
* Long-term safety for patients enrolled into the Extension Period.
* Incidence of hypophenylalaninemia (a blood Phe level <120 *mol/L); and
* Changes from baseline in vital signs and clinical laboratory parameters.
7. PopPK endpoints will include:
* CL/f (apparent clearance);
* V/f (apparent volume of distribution);
* AUC0-* (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);
8. PAH genotype.
Background summary
Phenylketonuria (PKU), an autosomal recessive condition, is a rare metabolic
disease caused by a mutation in the gene coding for phenylalanine hydroxylase
(PAH), a hepatic enzyme that converts the essential amino acid phenylalanine
(Phe) to tyrosine. Defects in the gene for PAH can lead to decreased conversion
of Phe to Tyr, progressive accumulation of Phe in the blood, and consequent
hyperphenylalaninemia (HPA) (8). Severe HPA is associated with neurotoxicity,
leading to neurodevelopmental delay in infants and young children and decreased
neurocognitive function in older children and adults. Clinically significant,
severe HPA due to defects in the PAH gene is referred to as PKU.
Virtually all cases of clinically significant HPA are detected in routine
newborn screening programs. In the neonatal period, concurrent with the process
for confirmation of the diagnosis of PKU, dietary Phe restriction is instituted
by limiting whole protein intake and providing Phe-free protein supplements to
meet nutritional needs for protein (9). Phe intake is limited to maintain blood
Phe levels within a clinically defined therapeutic target range that is above
normal blood Phe levels. Although dietary treatment has been proven to be
successful for prevention of severe neurodevelopmental delay, non-adherence to
treatment is very high in older children, adolescents and adults due to limited
practical feasibility of the often-severe protein restriction and poor
palatability of the Phe-free protein supplements (10).
Normal Phe levels in children vary with age and assay methodology. Reference
ranges for serum Phe determined by ion exchange chromatography at Mayo Medical
Laboratories (Rochester, MN, USA), a commonly used reference laboratory for
PKU, are 38-137 *mol/L for newborns (0-1 month old), 31-75 *mol/L for infants
(1 to 24 months old) and 26-91 *mol/L for older children and adolescents (2 to
18 years old) (11). Circulating Phe levels in untreated infants and children
with PKU following a normal diet are >360 *mol/L and can range to >2000 *mol/L.
Since low Phe levels can also be detrimental for growth and development, and
good clinical outcomes can be obtained even with blood Phe levels that are
slightly supranormal (12), therapeutic targets for treatment of children with
PKU do not aim for achievement of normal serum Phe levels. Instead, a usual
therapeutic target for children with PKU <4 years old is to maintain blood Phe
levels within a range of 120-360 *mol/L (defined as *120 to < 360 *mol/L) (8).
Study objective
Primary objectives of this study:
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 *mol/L (defined
as *120 to < 360 *mol/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 objectives of the study:
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.
Study design
Following Screening, eligible subjects will be randomized 1:1 to receive
either: (a) 10 mg/kg/day Kuvan® + a Phe-restricted diet or (b) just a
Phe-restricted diet over a 26-week Study Period.
It is intended that all subjects will maintain blood Phe levels within a range
of 120-360 *mol/L (defined as *120 to <360 *mol/L) through monitored dietary
intake during the 26-week Study Period. If after approximately 4 weeks, a
patient*s Phe tolerance has not increased by >20% vs. Baseline, the Kuvan® dose
will be increased in a single step to 20 mg/kg/day. A population
pharmacokinetics (PopPK) study is included in the Study Period, with collection
of baseline (pre-treatment) blood samples for measurement of endogenous BH4
levels. PopPK samplings will also be obtained during study Weeks 5-12,
inclusive.
After completing the Study Period, subjects will be eligible for enrolment in
the Extension Period, in which all subjects who continue in the study will
receive Kuvan® treatment + a Phe-restricted diet. For those patients randomized
to the Phe-restricted diet alone during the 26-week Study Period, their
starting Kuvan® dose in the Extension Period will be 10 mg/kg/day. A subject*s
treatment during the Extension Period will continue for 3 years or until
commercial product is approved and becomes available for <4 year-old patients
with PKU.
Intervention
Measuring Phe levels in blood (at the hospital + at home)
blood sampling for PopPK
BH4 responsiveness test
Study burden and risks
-
9, Chemin des Mines
CH-1201 Geneva
CH
9, Chemin des Mines
CH-1201 Geneva
CH
Listed location countries
Age
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 *mol/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 *mol/L (defined as *120 to < 360 *mol/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.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-015768-33-NL |
| ClinicalTrials.gov | NCT01376908 |
| CCMO | NL32785.068.10 |