E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Phenylketonuria |
Fenilcetonuria |
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E.1.1.1 | Medical condition in easily understood language |
Phenylketonuria: a genetic disease in which an enzyme defect leads to accumulation of a waste product (phenylketone) which can be detected in urine. |
Fenilcetonuria: una enfermedad genética en la que el déficit en una enzima conduce a la acumulación de un producto de deshecho (fenilcetona) que puede detectarse en orina. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
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 |
The purpose of this pilot trial is to assess the effect of sapropterin on the cognitive abilities of young adults with phenylketonuria (PKU). |
El propósito de este ensayo piloto es evaluar el efecto de la sapropterina en las habilidades cognitivas de jóvenes adultos con fenilcetonuria (FCU). |
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E.2.2 | Secondary objectives of the trial |
Not applicable. |
No aplicable. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Written informed consent given before any trial-related activities are carried out. -Women or men with documented PKU diagnosed by at least two Phe levels >or= 400 µmol/L. -Willingness to use a highly effective method of contraception is required during the study and follow-up periods. For women of childbearing potential: a negative urine pregnancy test is required at the end of screening. -Aged >or= 18 to 29 years, inclusive. -Mean blood Phe levels 600 to 1000 µmol/L during 12 months preceding inclusion in the study. The mean should be calculated from at least 3 blood Phe values over the last 12 months. Screening blood Phe level can be one of these values. There should be at least one value dated between Month -12 and -6 before screening and at least one value dated between Month -6 and screening. -An intelligence quotient (IQ) score >or= 85, assessed a maximum of 2 years before screening with an age appropriate Wechsler scale. If no IQ test result is available, IQ testing must be performed as part of screening using an age-appropriate Wechsler scale before the subject can be included. -Subjects willing to comply with all study procedures, including willingness to continue current dietary recommendations during the whole trial duration. |
-Consentimiento informado por escrito otorgado antes de la práctica de cualquier actividad del ensayo. -Mujeres u hombres con fenilcetonuria documentada, diagnosticada por como mínimo dos niveles de fenilalanina >o= 600 micromol/L -Conformidad en utilizar un método anticonceptivo altamente eficaz durante los periodos de estudio y de seguimiento. En las mujeres potencialmente fértiles se precisa una prueba de embarazo en orina negativa al término de la selección. -Edad >o= 18 a 29 años, ambos extremos incluidos. -Niveles hemáticos medios de fenilalanina de 600 a 1000 micromol/L durante los 12 meses previos a la entrada en el estudio. Se obtendrá el valor medio de como mínimo 3 determinaciones de fenilalanina en sangre a lo largo de los últimos 12 meses. Uno de estos valores podrá ser el nivel hemático de fenilalanina de la selección. Como mínimo, uno de los valores deberá haberse obtenido entre los Meses -12 y -6 antes de la selección y como mínimo un valor entre el Mes -6 y la selección -Una puntuación del coeficiente intelectual >o= 85, determinado un máximo de dos años antes de la visita de selección con una escala de Wechsler adecuada para la edad. Si no se dispusiera del resultado del coeficiente intelectual, este deberá determinarse como parte de la selección utilizando una escala de Wechsler adecuada para la edad antes de que se pueda incluir al sujeto en el estudio. -Los sujetos deberán estar de acuerdo en cumplir con todos los procedimientos del estudio, lo que incluye su conformidad en continuar con las recomendaciones dietéticas actuales durante todo el ensayo. |
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E.4 | Principal exclusion criteria |
-Subjects with tetrahydrobiopterin (BH4) deficiency. -Previous exposure to sapropterin or BH4 for > 30 days (or exposure to sapropterin or BH4 for <or= 30 days but within the previous 6 months prior to screening visit). -Subjects who, according to the Investigator, will not be able to comply with study procedures and computerized neuropsychological testing. -Any significant illness which, according to the Investigator, might preclude participation in the study (including neurological disease, cardio-vascular disease, history of seizure, predisposition to convulsions, renal or hepatic insufficiency, and active malignancy). -Any significant illness, medication or substance abuse which, according to the Investigator, might affect cognitive function and cognitive testing (e.g., significant visual or motor impairment, history of major head trauma, history of stroke, alcoholism, drug dependency, psychological disorder requiring chronic use of psychotropic medications such as anxiolytics, antidepressants, antipsychotic medication, mood stabilizers, and hypnotics). -Concomitant forbidden medication as described in the Kuvan® Summary of Product Characteristics, namely, inhibitors of dihydrofolate reductase (e.g., methotrexate, trimethoprim), medications that are known to affect nitric oxide synthesis (e.g., glyceryl trinitrate, isosorbide dinitrate, sodium nitroprusside, molsidomin, phosphodiesterase type 5 inhibitors, and minoxidil), and levodopa, as it may cause increased excitability and irritability. -Known hypersensitivity to sapropterin or any ingredients in the product´s formulation, or to other approved or non-approved formulations of BH4. -Subjects who have undergone cognitive neuropsychological testing similar to that to be performed as part of this trial with the following time limits: tasks with limited practice effect performed in the last 6 months, and tasks with important practice effect (such as tasks involving development of strategies) performed in the year preceding inclusion in the trial. Whether a task falls into one or the other category is left to Investigator judgment. -Female subjects who are pregnant or in the lactation period. -Subjects currently participating in another clinical trial or who participated in a previous clinical trial within 30 days prior to screening. -Legal incapacity or limited legal capacity. |
-Sujetos con deficiencia de BH4. -Exposición previa a sapropterina o BH4 durante > 30 días (o exposición a sapropterina o BH4 durante <o= 30 días pero dentro de los 6 meses previos a la visita de selección). -Sujetos que, según el investigador, no podrán cumplir con los procedimientos del estudio y con las pruebas neuropsicológicas informatizadas. -Toda enfermedad importante que, según el investigador, pueda impedir la participación en el estudio (como enfermedad neurológica, enfermedad cardiovascular, antecedentes de crisis convulsivas, predisposición a convulsiones, insuficiencia renal o hepática y proceso maligno activo). -Toda enfermedad importante, medicación o abuso de sustancias que, según el investigador, pueda afectar a la función cognitiva y a las pruebas cognitivas (por ejemplo, afectación visual o motora importante, antecedentes de traumatismo craneoencefálico mayor, antecedentes de ictus, alcoholismo, drogadicción, trastorno psicológico que precise el uso crónico de psicofármacos, como ansiolíticos, antidepresivos, antipsicóticos, estabilizadores del estado de ánimo e hipnóticos). -Medicación concomitante prohibida, según su descripción en la ficha técnica de Kuvan®, a saber, inhibidores de la dihidrofolato-reductasa (por ejemplo, metotrexato, trimetoprima), medicamentos que se sepa que afectan a la síntesis de óxido nítrico (por ejemplo, gliceril trinitrato, isosorbida dinitrato, nitroprusiato sódico, molsidomina, inhibidores de la fosfodiesterasa de tipo 5 y minoxidil) y levodopa, que puede provocar un aumento de la excitabilidad y la irritabilidad. -Hipersensibilidad conocida a la sapropterina o a cualquiera de los excipientes de la formulación del producto, o a cualquier otra formulación, aprobada o no, de BH4. -Sujetos que se han sometido a unas pruebas neuropsicológicas cognitivas similares a las que se deben practicar en este ensayo, con los siguientes límites de tiempo: tareas con efecto de práctica limitado efectuadas en los 6 últimos meses, y tareas con importante efecto de práctica (como tareas que implican el desarrollo de estrategias) realizadas en el año previo a la inclusión en el ensayo. El hecho de si una tarea pertenece a una u otra categoría quedará a criterio del investigador. -Mujeres que están embarazadas o en periodo de lactancia. -Sujetos que están participando actualmente en otro ensayo clínico o que han participado en un ensayo clínico previo en el plazo de los 30 días anteriores a la selección. -Incapacidad legal o capacidad legal limitada. |
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E.5 End points |
E.5.1 | Primary end point(s) |
As this trial is exploratory in nature, no statistical endpoints were defined as primary or secondary. |
Dado que este ensayo es de naturaleza exploratoria, no se ha definido ningún criterio de valoración principal o secundario. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Not applicable. |
No aplicable. |
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E.5.2 | Secondary end point(s) |
As this trial is exploratory in nature, no statistical endpoints were defined as primary or secondary. |
Dado que este ensayo es de naturaleza exploratoria, no se ha definido ningún criterio de valoración principal o secundario. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Not applicable. |
No aplicable. |
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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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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 | Yes |
E.8.2.3 | Other | No |
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
| 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 | 18 |
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 |
Belgium |
France |
Germany |
Italy |
Netherlands |
Spain |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 3 |
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 | 3 |