E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hyperphenylalaninemia due to phenylalanine hydroxylase deficiency. Phenotypes: classic phenylketonuria (PKU), mild PKU (MPK) or mild hyperphenylalaninemia (HPA). |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 81 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10034873 |
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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 aim of the study is to confirm the efficacy and safety of BH4 in the treatment of hyperphenylalaninemia caused by phenylalanine hydroxylase deficiency in patients responsive to BH4. The primary objective is to assess the effect of BH4 on phenylalanine tolerance compared to placebo under optimal blood phenylalanine control and to demonstrate safety in 12 months long-term treatment.
In patients younger than 10 years PK will be assessed. |
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Inclusion criteria for the screening phase 1. Female and male patients, aged 4-18 years 2. Phenylalanine-4-hydroxylase (PAH) deficiency shown by mutation analysis 3. Blood phenylalanine concentration in the 42-240 µmol/L for patients <10yrs otherwise 42-360 µmol/L range under dietary treatment 4. Achievement of phenylalanine equilibrium for at least 1 week before the screening phase 5. Written consent of patient (if only enough understand) and a parent or legal representative of the paediatric or adolescent patient after being given oral and written information on the study 6. Informed consent of the patient if she/he is able to understand the advantages/disadvantages of the participation in the study (this can be expected at a minimum age of 8 years). Written consent of an adolescent patient after oral and written information or oral consent procedure with an impartial witness is acceptable. 7. Assumed availability within the period of study participation 8. Patients/parents willing and able to follow the recommended diet 9. Use of an effective method of contraception in female patients of child bearing potential Inclusion criteria for the treatment phase 1. BH4-responsiveness determined by a combined phenylalanine-BH4 test (see Section 7.5.2 Combined phenylalanine-BH4-loading test) 2. Achievement of phenylalanine intake equilibrium for at least 1 week with subsequent determination of baseline phenylalanine tolerance (Phe-Tol0) |
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E.4 | Principal exclusion criteria |
BH4-deficiency due to genetic disorders in biosynthesis or recycling of BH4 History or current evidence of poor diet compliance History or current evidence of clinically relevant allergic or idiosyncratic reactions to drugs or food History of allergic reactions to BH4 or its excipients History or current evidence of any clinically relevant cardiovascular, pulmonary, renal, gastrointestinal, haematological, endocrinological, metabolic, neurological or other diseases as judged by the investigator History of malignancy within the past 5 years Relevant chronic or relevant current acute infections History of orthostatic deregulation, fainting or blackout Abuse of alcohol or drugs Positive pregnancy test (ß-HCG in serum) and lactating females Participation in other drug trials within the last 30 days before start for the study Patient already receiving BH4 treatment or who has received it within the last 1 month
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Endpoints: Dietary phenylalanine tolerance which will be assessed as the difference between the baseline phenylalanine tolerance (Phe-Tol0) and the phenylalanine tolerance at the end of BH4-treatment (Phe-Tol1). In patients younger than 10 years PK data will be assessed. Safety Endpoints: - Standard laboratory measurements, regular measurement of vital signs and the performance of physical examinations - Standard safety interview - Adverse events and serious adverse events - Deviance from blood phenylalanine target range evaluated by frequency and quantity
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
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) | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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 | Yes |
E.8.2.3 | Other | No |
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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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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At the end of 1 year of BH4 therapy patient will be given the opportunity to continue treatment under a compassionate- use protocol if the investigator feels it is appropriate, or to discontinue treatment. Either way, after 2 weeks a final study evaluation visit will be performed. |
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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 | |
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 | 2 |