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
Bron
Verkorte titel
Aandoening
PKU, KUVAN
Ondersteuning
1. University Medical Center Amsterdam
2. Academisch Ziekenhuis Maastricht
9, chemin des Mines
CH-1211 Geneva 20, Switzerland
Medical Responsible:
Agnès Champigneulle, MD, PhD
Senior Medical Director
Endocrinology Global Clin. Dvpt. Unit
Merck Serono S.A. – Geneva
9, chemin des Mines
CH-1202 Geneva, Switzerland
Phone: + 41 22 414 4278
Fax: + 41 22 414 3264
Onderzoeksproduct en/of interventie
Uitkomstmaten
Primaire uitkomstmaten
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.
Achtergrond van het onderzoek
N/A
Doel van het onderzoek
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 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)
EMR700773-003 Kuvan® in PKU Patients <4 Years Old.
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.
Onderzoeksopzet
Following Screening, eligible subjects will be
randomized 1:1 to receive either:
1. 10 mg/kg/day Kuvan® + a Phe-restricted diet;
2. Just a Pherestricted diet over a 26-week Study Period.
It is intended that all subjects will maintain blood Phe levels within a range of 120-360 μmol/L (defined as ≥120 to <360 μmol/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.
A repeated measures Analysis of Covariance
(ANCOVA) will be performed to assess the primary
endpoint, the treatment difference on Phe-tolerance
between 26 weeks (6 months) of Kuvan® + a Pherestricted diet vs. 26 weeks (6 months) of Pherestricted dietary therapy alone. A repeated measures ANCOVA model with baseline Phe tolerance and treatment, age group, visit, blood Phe level and treatment by visit interaction effects which has an unstructured covariance pattern will be considered to compare Phe tolerance at the 26-week (6-month visit) for the 2 treatment groups. Baseline Phe tolerance is defined as the Phe tolerance measured before the first
dose of Kuvan® in the 26-week Study Period.
Onderzoeksproduct en/of interventie
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.
Publiek
Wetenschappelijk
Belangrijkste voorwaarden om deel te mogen nemen (Inclusiecriteria)
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.
Belangrijkste redenen om niet deel te kunnen nemen (Exclusiecriteria)
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.
Opzet
Deelname
Opgevolgd door onderstaande (mogelijk meer actuele) registratie
Geen registraties gevonden.
Andere (mogelijk minder actuele) registraties in dit register
Geen registraties gevonden.
In overige registers
| Register | ID |
|---|---|
| NTR-new | NL3029 |
| NTR-old | NTR3177 |
| Ander register | Merck Serono S.A. – Geneva : EMR700773-003 |
| ISRCTN | ISRCTN wordt niet meer aangevraagd. |
Samenvatting resultaten
that will include data from all trial sites.
The Investigator will inform the Sponsor in advance about any plans to publish or present data
from the trial. Any publications and presentations of the results (abstracts in journals or
newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their
representatives, will require pre-submission review by the Sponsor.
The Sponsor will not suppress or veto publications but maintains the right to delay publication in
order to protect intellectual property rights.