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    EudraCT Number:2010-024311-13
    Sponsor's Protocol Code Number:EMR700773-004
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-10-01
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2010-024311-13
    A.3Full title of the trial
    A Multicenter, Double-Blind, Placebo Controlled, Randomized, 2-Arm Phase IIa Pilot Trial Assessing the Effect of Sapropterin on Cognitive Abilities in Young Adults with Phenylketonuria
    Ensayo piloto de fase IIa, multicéntrico, en doble ciego, controlado con placebo, aleatorizado y de 2 grupos, para evaluar el efecto de la sapropterina sobre las capacidades cognitivas en adultos jóvenes con fenilcetonuria
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study, carried out in different centers and using a placebo, to assess the effect of a medicinal product, containing sapropterin as the active substance, on mental abilities in young adults suffering from phenylketonuria, a genetic disease in which an enzyme defect leads to accumulation of a waste product (phenylketone) which can be detected in urine.
    Estudio clínico, llevado a cabo en diferentes centros y usando placebo, para evaluar el efecto de un producto medicinal, que contiene sapropterina como sustancia activa, en las habilidades mentales en jóvenes adultos que sufren 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.
    A.3.2Name or abbreviated title of the trial where available
    SIGNAL (SapropterIn on coGnitive abilities in youNg Adults with phenyLketonuria)
    SIGNAL (SapropterIna en la habilidad coGnitiva de jóveNes Adultos con feniLcetonuria)
    A.4.1Sponsor's protocol code numberEMR700773-004
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck KGaA
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck KGaA
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Center Merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.4Telephone number+496151725200
    B.5.5Fax number+496151722000
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Kuvan®
    D. of the Marketing Authorisation holderMerck Serono Europe Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/04/199
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSapropterin
    D.3.9.1CAS number 62989-33-7
    D.3.9.3Other descriptive nameSAPROPTERIN DIHYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB27757
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCoated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    E.1.1.1Medical 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.
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10034873
    E.1.2Term Phenylketonuria (PKU)
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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).
    E.2.2Secondary objectives of the trial
    Not applicable.
    No aplicable.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Not applicable.
    No aplicable.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Not applicable.
    No aplicable.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 27
    F.4.2.2In the whole clinical trial 30
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None (standard treatment for phenylketonuria should be continued in accordance with the trial site's standard-of-care and generally accepted medical practices and depending on the subject's individual medical needs).
    Ninguna (continuará el tratamiento habitual de la fenilcetonuria de acuerdo con la práctica habitual del centro del ensayo y la práctica médica generalmente aceptada, y en función de las necesidades médicas concretas del sujeto.)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-11-04
    P. End of Trial
    P.End of Trial StatusCompleted
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