E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10034873 |
E.1.2 | Term | Phenylketonuria (PKU) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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.
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E.2.2 | Secondary objectives of the trial |
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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | 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.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | 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 occipital-frontal 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-∞ (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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the end of study part (26 weeks) or at the end of the extension period |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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•all enrolled subjects who have received at least one dose of study drug have completed all scheduled visits
•follow-up of all subjects with ongoing adverse events at the conclusion of treatment has been addressed
•site monitoring visits to resolve any outstanding data discrepancy issues have been completed for all participating centres
•the database has been locked
•all sites have undergone a final site closure/study termination visit
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |