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    EudraCT Number:2012-002436-82
    Sponsor's Protocol Code Number:EC11-441
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-10-22
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2012-002436-82
    A.3Full title of the trial
    Melatonin effects on visual and sleep patterns anomalies in subjects diagnosed with Retinitis Pigmentosa
    Efecto de la melatonina sobre las alteraciones visuales y del sueño en enfermos afectos de Retinosis Pigmentaria
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Melatonin effects on visual and sleep patterns anomalies in subjects diagnosed with Retinitis Pigmentosa
    Efecto de la melatonina sobre las alteraciones visuales y del sueño en enfermos afectos de Retinosis Pigmentaria
    A.4.1Sponsor's protocol code numberEC11-441
    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 SponsorIsabel Pinilla Lozano
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMinisterio de Sanidad, Política Social e Igualdad
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstituto Aragonés de Ciencias de la Salud
    B.5.2Functional name of contact pointEva López Hernández
    B.5.3 Address:
    B.5.3.1Street AddressAvda. San Juan Bosco 13, Planta 1ª
    B.5.3.2Town/ cityZaragoza
    B.5.3.3Post code50009
    B.5.4Telephone number34976716982
    B.5.5Fax number34976715554
    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 CIRCADIN 2 mg comprimidos de liberación prolongada
    D. of the Marketing Authorisation holderNEURIN PHARMACEUTICALS LTD.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCircadin 2 mg
    D.3.4Pharmaceutical form Prolonged-release 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 INNNot answered
    D.3.9.1CAS number 73-31-4
    D.3.9.2Current sponsor codeNot answered
    D.3.9.3Other descriptive nameMELATONIN
    D.3.9.4EV Substance CodeSUB14496MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 placeboProlonged-release capsule
    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
    To evaluate the sleep quality in patients with Retinitis Pigmentosa
    Evaluar la calidad del sueño en pacientes con RP
    E.1.1.1Medical condition in easily understood language
    To evaluate the sleep quality in patients with Retinitis Pigmentosa
    Evaluar la calidad del sueño en pacientes con RP
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To establish the therapeutic effect of melatonin, orally administered, on visual and sleep disturbances in adults patients affected by Retinitis Pigmentosa.
    Establecer la eficacia terapeútica de la melatonina, administrada por vía oral, sobre las alteraciones visuales y del sueño que sufren los pacientes adultos con Retinosis Pigmentaria.
    E.2.2Secondary objectives of the trial
    To evaluate the protective effect of melatonin, orally administered, in patients with Retinitis Pigmentosa, measuring the following parameters:
    1.Sleep quality assesses by means of Sleep Quality questionnaires
    2.Rest-activity cycles monitored by actigraph recording.
    3.Oxidative stress quantified by measurement of malondialdehyde and 4- hydroxyalkenals, protein carbonyl, nitrites, total antioxidant status, melatonin, and activities of catalase, glutathione reductase, glutathione peroxidase, and superoxide dismutase.
    4.Visual function assessed by Visual function best corrected visual acuity ETDRS scale or low vision ones, Funduscopy evaluation, Macular and Retinal Nerve Fiber Layer measured by Spectral Domain Optical Coherence Tomography, Electoretinogram (ERG) and automated perimetry.
    5.Life quality evaluated by the National Eye Institute Visual Functioning Questionnaire.25 (NEI VFQ-25)
    Evaluar el efecto protector de la melatonina, administrada por vía oral a los pacientes con Retinosis Pigmentaria, mediante los siguientes parámetros:
    1.Calidad del sueño, valorada mediante los cuestionarios de calidad de sueño.
    2.Ritmo sueño-vigilia, cuantificado mediante el registro actimétrico.
    3.Estado oxidativo, cuantificado mediante la determinación de cuantificación de malonildialdehido y 4-hidroxialquenales, restos carbonilo de las proteínas, nitritos, melatonina, actividad total antioxidante y de la superóxido dismutasa, catalasa, glutation reductasa y glutation peroxidasa.
    4.Función visual, valorada mediante test de AV con optotipos ETDRS u optotipos de baja visión, evaluación del Fondo de Ojo mediante fundoscopia y OCT macular, ERG y perimetría automatizada.
    5.Calidad de vida del enfermo, valorada mediante los cuestionarios de calidad de vida del enfermo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a)Patients from de Ophthalmology Department
    b)Being 18 years old or older
    c)Diagnosed with Retinitis Pigmentosa
    d)Visual acuity equal or less than 20/200
    e) In case of any other pathologies, treated with the standard treatment following the international directions and the protocols established by the Ophthalmic Unit
    f)Signed informed consent
    a)Paciente del Servicio de Oftalmología
    b)Edad igual o superior a 18 años
    c)Cumplimiento de los criterios diagnósticos de Retinosis Pigmentaria
    d)Con Agudeza Visual (AV) igual o inferior a 20/200
    e)Recibir el tratamiento estándar, en caso de existir otras patologías, de acuerdo con las directrices universalmente aceptadas y con los protocolos del Servicio de Oftalmología
    f)Consentimiento informado firmado
    E.4Principal exclusion criteria
    a) No informed consent
    b) Absence of other ophthalmological treatments if needed
    c) Patients affected by atypical forms of Retinitis Pigmentosa as sector or paravenous forms, Bardet Biedl or Refsum syndromes, or Retinitis punctata albescens.
    d) Patients with other systemic pathologies or deafness (excluding Usher syndrome)
    e) Pregnancy (or a likelihood of becoming pregnant) or lactation.
    f) Patients with other retinal diseases
    a)Ausencia de consentimiento informado
    b)Ausencia de tratamiento oftalmológico por patologías concomitantes
    c)Paciente con formas ati?picas de Retinosis Pigmentaria (como formas en sector, paravenosas, sindrome de Bardet-Bield y de Refsum y Retinitis Puntata Albecens).
    d)Paciente con otras patologi?as siste?micas o sordera (exceptuando Síndrome de Usher).
    e)Embarazadas o con posibilidad de estarlo o en lactancia
    f)Paciente que asocia otras patologi?as retinianas intercurrentes.
    E.5 End points
    E.5.1Primary end point(s)
    -Sleep quality assessed by means of the Pittsburg Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and the Horne and Ostberg Morningness/Eveningness Questionnaire.
    -Life quality evaluated by the National Eye Institute Visual Functioning Questionnaire.25 (NEI VFQ-25)
    -Rest-activity cycles monitored by an actimeter that the patient wears like a wristwatch, recording the amount of movement made and the radiation of light received versus time.
    -Oxidative stress parameters measured in blood:
    a. Quantification of malondialdehyde and 4- hydroxyalkenals (MDA+4-HDA) by colorimetric methods. Blood levels of MDA+4-HDA are an index of lipid peroxidation.
    b. Protein carbonyl content: following the methodology of Levine. The protein carbonyl content is a marker of oxidative damage to proteins.
    c. Nitrites: by colorimetric method. Levels of nitrites formed after reaction of reactive nitrogen species with macromolecules are used as a marker of nitrosative stress.
    d. Total antioxidant activity (TAS): measuring the ability of plasma to inhibit the oxidation of 2,2?-Azino-bis-(3-ethyl-benzthiazoline-6-sulfonic acid) (ABTS) by metamyoglobin and hydrogen peroxide to form the radical cation ABTS? +.
    e. Superoxide dismutase activity (SOD): calculating the inhibition ratio of reduction of cytochrome C by the superoxide radical (? O2-), determined at 550 nm.
    f. Catalase activity (CAT): by following the decrease in the concentration of hydrogen peroxide (H2O2).
    g. Glutathione reductase activity (GRD): by oxidation of NADPH to NADP+ in the presence of oxidized glutathione, following the decrease in absorbance at ? = 340 nm for 3 minutes, as described by Goldberg and Spooner.
    h. Glutathione peroxidase activity (GP): using the colorimetric kit (Oxis Research, Foster CA) that follows the steady decline in the concentration of NADPH as reduced glutathione levels remain constant.
    i. Melatonin: using the melatonin radioimmunoassay kit (DLD Diagnostika GmbH, Hamburg, Germany).
    -Visual function: best corrected visual acuity evaluated by Early Treatment Diabeic retinopahty Study (ETDRS) scale or low vision ones, Funduscopy evaluation, Macular and Retinal Nerve Fiber Layer thicknesses measured by Spectral Domain Optical Coherence Tomography using Spectralis OCT (Heidelberg, Germany), at the different macular areas described by ETDRS, Electoretinogram (ERG) and automated perimetry.
    Calidad del sueño, valorada mediante los cuestionarios de calidad de sueño de Pittsburg (Pittsburg Sleep Quality Index, PSQI), Escala de Somnolencia de Epworth y cuestionario de tipología circadiana de Horne & Ostberg.
    - Calidad de vida, valorada mediante los cuestionarios de calidad de vida de NEI-VFQ-25
    - Ritmo sueño-vigilia, monitorizado mediante un actímetro que se coloca en la muñeca del paciente, al estilo de un reloj, registrando la cantidad de movimiento realizado y la radiación lumínica recibida en función del tiempo.
    - Párametros de estado oxidativo que se determinarán en plasma:
    a. Cuantificación de malonildialdehido y 4-hidroxialquenales (MDA+4- HDA): mediante método colorimétrico. Las concentraciones de MDA+4-HDA son un indicador del grado de peroxidación de los lípidos.
    b. Restos carbonilo de las proteínas: siguiendo la metodología de Levine. Los restos carbonilo son un marcador del daño oxidativo a las protéinas.
    c. Nitritos: mediante método colorimétrico. Los niveles de nitritos formados tras la reacción de las especies reactivas de nitrógeno con las macromoléculas de la célula permiten cuantificar el estado nitrosativo de la misma.
    d. Actividad total antioxidante (TAS): midiendo la capacidad del plasma de inhibir la oxidación del 2,2'-azino-bis-(ácido 3-etil-benzotiazolina-6-sulfónico) (ABTS) por la metamioglobina y peróxido de hidrógeno para formar el catión radical ABTS?+.
    e. Actividad de la superóxido dismutasa (SOD): calculando la inhibición del ratio de reducción del citocromo C por el radical superóxido (?O2-), determinado a 550 nm.
    f. Catalasa (CAT): siguiendo el descenso en la concentración de peróxido de hidrógeno (H2O2).
    g. Glutatión reductasa (GRd), mediante la oxidación de NADPH a NADP+, en presencia de glutation oxidado, siguiendo el descenso en la absorbancia a ?=340 nm durante 3 minutos, como describieron Goldberg y Spooner.
    h. Glutatión peroxidada (GP): observando el continuo descenso en la concentración de NADPH mientras los niveles de glutatión reducido se mantienen constantes. La medición se realizará utilizando el kit colorimétrico (Oxis Research, Foster CA).
    i. Melatonina: se realizará mediante el kit de radioinmunoensayo de melatonina (DLD Diagnostika GmbH, Hamburg, Alemania).
    - Función visual, valorada mediante test de AV con optotipos ETDRS u optotipos de baja visión, evaluación del Fondo de Ojo mediante fundoscopia y OCT de dominio espectral utilizando el Spectralis OCT, (Heidelberg, Alemania) macular y de nervio óptico valorando las diferentes áreas descritas en el ETDRS y el espesor de la capa de fibras nerviosas de la retina peripapilar, Electrorretinograma (ERG) y perimetría automatizada.
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the 13 weeks of the follow up time. For more information check the schedule of events
    Durante las 13 semanas del período de seguimiento. Para más información consultar el protocolo
    E.5.2Secondary end point(s)
    E.5.2.1Timepoint(s) of evaluation of this end point
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Last patient last visit
    Última visita del último paciente reclutado en el estudio
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 80
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state80
    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)
    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 Decision2012-12-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-10
    P. End of Trial
    P.End of Trial StatusOngoing
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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