E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects diagnosed with Phenylketonuria (PKU) (classic or mild PKU, or mild hyperphenylalaninaemia (HPA)). |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10034873 |
E.1.2 | Term | Phenylketonuria (PKU) |
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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 |
The primary objective of the study is to evaluate the proportion of responders (≥30% reduction from baseline in blood Phe level) to 20 mg/kg/day Sapropterin dihydrochloride treatment at several time points during 28 days. |
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E.2.2 | Secondary objectives of the trial |
The main secondary endpoints include: Incidence of adverse reactions and their severity, abnormal laboratory values. The proportion of early responders, late responders, partial responders and non responders. The difference between the proportion of patients positive for any PAH mutation measured versus patients negative for the corresponding PAH mutation and observed for safety and efficacy clinical endpoints. Proportion of subjects categorized after phenotype. Mean change in Phe level in subjects categorized after phenotype from baseline to all testing time points. Mean change in Phe and tyrosine blood levels and blood Phe-to-tyrosine ratio in subjects categorized after phenotype from baseline to all testing time points. Proportion of subjects with a Phe level less than 120µmol/l for at least one testing time point during the study period according to response status (early, late, partial or non). To assess differences in age groups in safety and efficacy clinical endpoints |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•aged 4 years or older at the time the informed consent is obtained •diagnosed with PKU (subgroups defined as: classic PKU [blood Phe >1200 µmol/L], mild PKU [blood Phe 600–1200 µmol/L] or mild HPA [blood Phe 300–600 µmol/L] •have received no previous treatment with sapropterin dihydrochloride (either Kuvan® or any other formulations of tetrahydrobiopterin) •adherent to diet and willing to adhere to the given diet for the 4 weeks study period •Provide a signed (by parent if below 18 years) written informed consent. •genotyped for PAH mutations (PKU genotype)
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E.4 | Principal exclusion criteria |
•have documented BH4 deficiency •have any contraindications to receive Kuvan® as outlined in the SmPC not willing or able to comply with the study procedures •be pregnant, planning pregnancy or breastfeeding •have been exposed to any investigational medicinal drugs or treatments within 30 days or 5 half lives, whichever is longer, prior to the screening visit •using concomitant treatment with folate synthesis inhibiting drugs •concurrent use of Levodopa •concurrent use of inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim) •concurrent use of agents that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodistrerase type 5 (PDE-5) inhibitors and monoxidil •have a concurrent disease potentially interfering safety (e.g. seizure disorder, oral steroid dependent asthma, other conditions requiring systemic corticosteroids, or insulin-dependent diabetes mellitus) •have inadequate liver function, defined by alanine aminotransferase (ALT) 2 x upper limit of normal (ULN) •have clinically significant renal dysfunction, defined by serum creatinine > 250 µmol/l •Have any medical condition that, in the judgment of the investigator, would jeopardize the patient’s safety following exposure to study drug or would significantly interfere with the patient’s ability to comply with the provisions of this protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this trial is the proportion of subjects with at least 30% reduction from baseline in blood Phe level (responders) in any blood sample during the 28 days treatment with 20 mg/kg/day Kuvan®. |
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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 | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |