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    EudraCT Number:2018-004406-25
    Sponsor's Protocol Code Number:IB1001-202
    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:2019-04-12
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2018-004406-25
    A.3Full title of the trial
    Effects of N-Acetyl-L-Leucine on GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease): A multinational, multicenter, open-label, rater-blinded Phase II study.
    Efectos de N-acetil-L-leucina en Gangliosidosis GM2 (enfermedad de Tay-Sachs y Sandhoff): un ensayo en fase II multinacional, multicéntrico, sin enmascaramiento para los pacientes y con enmascaramiento para los evaluadores.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A safety and efficacy study of N-Acetyl-L-Leucine on GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease).
    Un ensayo sobre la eficacia y la seguridad de N-acetil-L-leucina en Gangliosidosis GM2 (enfermedad de Tay-Sachs y Sandhoff)
    A.4.1Sponsor's protocol code numberIB1001-202
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03759665
    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 SponsorIntraBio Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportIntraBio Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIntraBio Ltd
    B.5.2Functional name of contact pointTaylor Fields
    B.5.3 Address:
    B.5.3.1Street AddressBegbroke Science Park, Begbroke Hill, Woodstock Road
    B.5.3.2Town/ cityBegbroke, Oxfordshire
    B.5.3.3Post codeOX5 1PF
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4401865309689
    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 No
    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/3/17/1949
    D.3 Description of the IMP
    D.3.1Product nameN-Acetyl-L-Leucine
    D.3.2Product code IB1001
    D.3.4Pharmaceutical form Powder for oral suspension
    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 INNN Acetyl L leucine
    D.3.9.2Current sponsor codeIB1001
    D.3.9.3Other descriptive name2(S)-(ACETYLAMINO)-4-METHYLPENTANOIC ACID
    D.3.9.4EV Substance CodeSUB195712
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number2 to 4
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease)
    Gangliosidosis GM2 (enfermedad de Tay-Sachs y Sandhoff)
    E.1.1.1Medical condition in easily understood language
    GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease)
    Gangliosidosis GM2 (enfermedad de Tay-Sachs y Sandhoff)
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10010331
    E.1.2Term Congenital, familial and genetic disorders
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on blinded raters’ clinical impression of change in severity (CI-CS) in the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease).
    El objetivo principal es evaluar la eficacia de N-acetil-L-leucina en el tratamiento de la Gangliosidosis GM2 (enfermedad de Tay-Sachs y Sandhoff) a partir de la impresión clínica del cambio de gravedad (CI-CS) en evaluadores a quienes se oculta el tratamiento
    E.2.2Secondary objectives of the trial
    To assess the clinical efficacy of N-Acetyl-L-Leucine on symptoms of ataxia, functioning, and quality of life for patients with GM2 Gangliosidosis;

    To evaluate the safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in patients with GM2 Gangliosidosis, including patients aged ≥18 years in the United States and patients aged ≥13 years in Europe, and weight-tiered doses in patients 6 to 12 years of age in Europe
    Evaluar la eficacia clínica de N-Acetil-L-Leucina en los síntomas de ataxia, el funcionamiento y la calidad de vida de los pacientes con Gangliosidosis GM2;

    Evaluar la seguridad y tolerabilidad de N-Acetil-L-Leucina de 4 g / día en pacientes con Gangliosidosis GM2, incluidos pacientes de ≥18 años en los Estados Unidos y pacientes de ≥13 años en Europa y dosis por peso en pacientes 6 - 12 años de edad en Europa
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Written informed consent signed by the patient and/or their legal representative/ parent

    2.Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of GM2 Gangliosidosis at the time of signing informed consent. Confirmed diagnosis, i.e., clinical features and positive genetic test GM2-gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes

    3.Females of childbearing potential, defined as a premenopausal female capable of becoming pregnant, will be included if they are either sexually inactive (sexually abstinent for 14 days prior to the first dose and confirm to continue through 28 days after the last dose) or using one of the following highly effective contraceptives (i.e. results in <1% failure rate when used consistently and correctly) 14 days prior to the first dose continuing through 28 days after the last dose:
    a)intrauterine device (IUD);
    b)surgical sterilization of the partner (vasectomy for 6 months minimum);
    c)combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal);
    d)progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable);
    e)intrauterine hormone releasing system (IUS);
    f)bilateral tubal occlusion.

    4.Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose:
    a)hysteroscopic sterilization;
    b)bilateral tubal ligation or bilateral salpingectomy;
    d)bilateral oophorectomy;
    OR be postmenopausal with amenorrhea for at least 1 year prior to the first dose and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status. FSH analysis for postmenopausal women will be done at screening. FSH levels should be in the postmenopausal range as determined by the central laboratory.

    5.Non-vasectomized male patient agrees to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study medication and the female partner agrees to comply with inclusion criteria 3 or 4. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non-vasectomized male.

    6.If male, patient agrees not to donate sperm from the first dose until 90 days after their last dose.

    7.Patients must fall within:
    a)A SARA score of 5 ≤ X ≤ 33 points (out of 40)
    i.Within the 2-7 range (0-8 range) of the Gait subtest of the SARA scale
    ii.Be able to perform the 9-Hole Peg Test with Dominant Hand (9HPT-D) (SCAFI subtest) in 20 ≤ X ≤150 seconds.

    8.Weight ≥15 kg at screening.

    9.Patients are willing to disclose their existing medications/therapies for (the symptoms) of GM2 Gangliosidosis, including those on the prohibited medication list. Non-prohibited medications/therapies (e.g. concomitant speech therapy, and physiotherapy) are permitted provided:
    a)The Investigator does not believe the medication/therapy will interfere with the study protocol/results
    b)Patients have been on a stable dose/duration and type of therapy for at least 6 weeks before Visit 1 (Baseline 1)
    c)Patients are willing to maintain a stable dose/do not change their therapy throughout the duration of the study.

    10.An understanding of the implications of study participation, provided in the written patient information and informed consent by patients or their legal representative/parent, and demonstrates a willingness to comply with instructions and attend required study visits (for children this criterion will also be assessed in parents or appointed guardians).
    1.Consentimiento informado por escrito y firmado por el paciente o su representante legal o padre/madre

    2.Paciente masculino o femenino ≥ 6 años en Europa O BIEN ≥18 años en Estados Unidos con un diagnóstico confirmado de Gangliosidosis GM2 en el momento de firmar el consentimiento informado. Diagnóstico confirmado, es decir, características clínicas y prueba genética positiva GM2-gangliosidosis causada por deficiencia de β-hexosaminidasa resultante de mutaciones en el gen HEXA o HEXB

    3.Se incluirá a las mujeres en edad fértil, definidas como mujeres premenopáusicas capaces de quedarse embarazadas, si son sexualmente inactivas (sin relaciones sexuales durante 14 días antes de la primera dosis y confirman que continuarán hasta 28 días después de la última dosis) o si utilizan uno de los siguientes métodos anticonceptivos de alta eficacia (es decir, si se usa de manera consistente y correcta, la tasa de ineficacia es <1 %) 14 días antes de la primera dosis y hasta 28 días después de la última dosis:
    a)Dispositivo intrauterino (DIU).
    b)Esterilización quirúrgica del compañero (vasectomía de 6 meses como mínimo).
    c)Método anticonceptivo hormonal combinado (que contiene estrógeno o progestágeno) asociado con la inhibición de la ovulación (ya sea oral, intravaginal o transdérmico).
    d)Anticoncepción hormonal con únicamente progestágeno asociada con la inhibición de la ovulación (ya sea oral, inyectable o implantable).
    e)Sistema de liberación hormonal intrauterino (SIU).
    f)Ligadura/oclusión de trompas bilateral.

    4.Las mujeres que no están en edad fértil deben haber sido sometidas a una de las siguientes intervenciones de esterilización al menos 6 meses antes de la primera dosis:
    a)esterilización histeroscópica;
    b)ligadura de trompas bilateral o salpingectomía bilateral;
    d)ooforectomía bilateral;
    O BIEN estar posmenopáusica con amenorrea durante al menos un año antes de la primera dosis y presentar niveles séricos de la hormona foliculoestimulante (FSH) compatibles con el estado posmenopáusico. Los análisis de FSH en las mujeres posmenopáusicas deben hacerse durante la selección. Los niveles de FSH deben situarse en el intervalo posmenopáusico, tal y como sea determinado por el laboratorio central.

    5.Los pacientes masculinos no vasectomizados aceptan usar un preservativo con espermicida o abstenerse de tener relaciones sexuales durante el estudio hasta 90 días después de la última dosis de la medicación del estudio y la pareja femenina acepta cumplir con los criterios de inclusión 3 o 4. Para los pacientes masculinos vasectomizados que se hayan sometido a la intervención 6 meses antes (o más) del inicio del estudio, se requiere que usen preservativo durante la relación sexual. Si el paciente masculino ha sido sometido a la vasectomía en un período menor a 6 meses antes del inicio del estudio, debe cumplir las mismas restricciones que un varón no vasectomizado.

    6.Si es un paciente masculino, debe aceptar no donar esperma desde la primera dosis hasta 90 días después de la última dosis.

    7.Los pacientes deben cumplir los parámetros siguientes:
    a)Una puntuación de SARA de 5 ≤ X ≤ 33 puntos (sobre 40)
    b)O bien:
    i.En el intervalo 2-7 (del intervalo 0-8) de la prueba secundaria de marcha de la escala SARA
    O BIEN
    ii.Ser capaz de llevar a cabo la prueba del clavijero con nueve orificios de la mano dominante (PC9O-MD) (prueba secundaria de SCAFI) en 20 ≤ X ≤150 segundos.

    8.Peso ≥15 kg durante la selección.

    9.Los pacientes están dispuestos a revelar sus medicamentos/tratamientos actuales para (los síntomas) de la Gangliosidosis GM2, incluyendo los de la lista de medicamentos prohibidos. Se permite el uso de medicamentos o terapias prohibidas (p. ej., foniatría/logopedia concomitante y fisioterapia) en caso de que:
    a)El investigador no crea que la medicación o la terapia interfieran en los resultados o el protocolo del ensayo
    b)Los pacientes mantengan una dosis o una duración y un tipo de terapia estable durante al menos 6 semanas antes de la visita 1 (valoración inicial 1)
    c)Los pacientes estén dispuestos a mantener una dosis estable o a no cambiar su terapia durante la duración del estudio.

    10.Una comprensión de las implicaciones de la participación en el estudio, proporcionada en la información por escrito del paciente y el consentimiento informado por parte de los pacientes o de su representante legal/padres, y que demuestre la voluntad de cumplir con las instrucciones y de asistir a las visitas de estudio requeridas (en el caso de los niños, este criterio también se evaluará en los padres o tutores designados).
    E.4Principal exclusion criteria
    Individuals who meet any of the following criteria are not eligible to participate in the study:
    1.Asymptomatic patients

    2.Patient has clinical features of Tay-Sachs or Sandhoff disease, but a completely negative result on a previous genetic test for GM2 Gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes

    3.Patients who have any of the following:
    a)Chronic diarrhea;
    b)Unexplained visual loss;
    d)Insulin-dependent diabetes mellitus.
    e)Known history of hypersensitivity to the Acetyl-Leucine (DL-, L-, D-) or derivatives.
    f)History of known hypersensitivity to excipients of Ora-Blend® (namely sucrose, sorbitol, cellulose, carboxymethylcellulose, xanthan gum, carrageenan, dimethicone, methylparaben, and potassium sorbate).

    4.Simultaneous participation in another clinical study or participation in any clinical study involving administration of an investigational medicinal product (IMP; ‘study drug’) within 6 weeks prior to Visit 1.

    5.Patients with a physical or psychiatric condition which, at the investigator’s discretion, may put the patient at risk, may confound the study results, or may interfere with the patient’s participation in the clinical study.

    6.Known clinically-significant (at the discretion of the investigator) laboratories in hematology, coagulation, clinical chemistry, or urinalysis, including, but not limited to:
    a.Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x upper limit of normal (ULN);
    b.Total bilirubin >1.5x ULN, unless Gilbert’s syndrome is present in which case total bilirubin >2x ULN.

    7.Known or persistent use, misuse, or dependency of medication, drugs, or alcohol.

    8.Current or planned pregnancy or women who are breastfeeding.

    9.Patients with severe vision or hearing impairment (that is not corrected by glasses or hearing aids) that, at the investigator’s discretion, interferes with their ability to perform study assessments.

    10.Patients who have been diagnosed with arthritis or other musculoskeletal disorders affecting joints, muscles, ligaments, and/or nerves that by themselves affects patient’s mobility and, at the investigator’s discretion, interferes with their ability to perform study assessments.
    11.Patients unwilling and/or not able to undergo a 6-week washout period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6.
    a)Aminopyridines (including sustained-release form);
    b)N-Acetyl-DL-Leucine (e.g. Tanganil®);
    c)N-Acetyl-L-Leucine (prohibited if not provided as IMP);
    No se incluirá a un paciente en el estudio en caso de poderle aplicar uno o más de los criterios siguientes:
    1.Pacientes asintomáticos

    2.El paciente tiene características clínicas de la enfermedad de Tay-Sachs o Sandhoff gangliosidosis, pero un resultado completamente negativo en una prueba genética previa para la gangliosidosis GM2 causada por deficiencia de β-hexosaminidasa resultante de mutaciones en el gen HEXA o HEXB

    3.Pacientes que presentan alguno de los siguientes síntomas:
    a)Diarrea crónica.
    b)Pérdida de la visión sin causa aparente.
    c)Neoplasias malignas.
    d)Diabetes mellitus de tipo 1 (insulinodependiente).
    e)Antecedentes de hipersensibilidad conocida a acetil-leucina (DL-, L-, D-) o derivados.
    f)Antecedentes de hipersensibilidad conocida a Ora-Blend® (es decir, a sacarosa, sorbitol, celulosa, carmelosa, goma xantana, carragenina, dimeticona, metilparabeno y sorbato de potasio).

    4.Participación simultánea en otro ensayo clínico o en cualquier estudio clínico que implique la administración de un medicamento en investigación (MI, «fármaco del estudio») en el plazo de 6 semanas antes de la visita 1.

    5.Pacientes con una afección física o psiquiátrica que, a juicio del investigador, pueda conllevarles un riesgo, pueda alterar los resultados del estudio, o bien pueda interferir en su participación en el estudio clínico.

    6.Pruebas analíticas clínicamente significativas conocidas (a juicio del investigador) en hematología, coagulación, bioquímica clínica o análisis de orina, incluyendo, pero sin limitación:
    a.Aspartato-transaminasa (AST) o alanina-transaminasa (ALT) >5 veces al límite superior de la normalidad (LSN);
    b.Bilirrubina total >1,5 veces al LSN, a menos que esté presente el síndrome de Gilbert, en cuyo caso la bilirrubina total >2 veces al LSN.

    7.Ingesta, mal uso o dependencia conocida o persistente de medicamentos, drogas o alcohol.

    8.Embarazo actual o previsto o bien mujeres en lactancia materna.

    9.Pacientes con problemas importantes de visión o audición (que no se corrigen con gafas o audífonos) que, a criterio del investigador, interfieran en su capacidad de realizar evaluaciones del estudio.

    10.Pacientes diagnosticados de artritis u otros trastornos musculoesqueléticos que afecten a las articulaciones, ligamentos o nervios y que por sí solos afecten a la movilidad del paciente y, a criterio del investigador, interfieran en su capacidad de realizar las evaluaciones del estudio.

    11.Pacientes que no deseen o no puedan someterse a un período de reposo farmacológico de 6 semanas de cualquiera de los siguientes medicamentos prohibidos antes de la visita 1 (valoración inicial 1) y sigan sin utilizar medicamentos prohibidos en la visita 6.
    a)Aminopiridinas (incluidas las formulaciones de liberación prolongada). b)N-acetil-DL-leucina (p. ej., Tanganil®).
    c)N-acetil-L-leucina (prohibido si no se administra como MI).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint for the study is based on blinded raters’ Clinical Impression of Change in Severity (CI-CS) comparing videos showing the patient’s change in performance over 6 weeks on a pre-defined anchor clinical symptom scale: either the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or the 8 Meter Walk Test (8MWT).
    The comparison of the Visit 4 video with the Visit 2 video and the comparison of the Visit 6 video with the Visit 4 video will provide the scores that contribute to the primary endpoint. Each of these comparisons will score change on a 7-point Likert scale (+3=significantly improved to -3= significantly worse).
    During the pre-treatment period, the treating physician will evaluate each patient’s clinical symptoms and select, at Visit 1, either the 9HPT-D or 8MWT as the primary anchor around which the CI-CS assessment will be scored. A cognitive assessment should be performed at Visit 1 according to standard procedures of the clinical site to assist with the selection of the anchoring functional test appropriate for each patient from both a cognitive and a motor perspective.
    The primary evaluation of the CI-CS will be performed by two independent neurologists whose assessments will be based on videos of the anchor test taken at each visit. These raters will be blinded to the treatment periods (baseline, treatment, or washout) to reduce detection and performance bias.
    The primary endpoint is defined as the CI-CS comparing end of treatment with N-Acetyl-L-Leucine (Visit 4) with baseline (Visit 2) minus the CI-CS comparing the end of washout (Visit 6) with the end of treatment with N-Acetyl-L-Leucine (Visit 4).
    The CI-CS assessment will instruct the blinded rater to consider: ‘compared to the first video, how has the severity of their performance on the 9HPT-D or 8MWT changed (improved or worsened) in 6-weeks as observed in the second video?’
    It is expected that the blinded observers will reach agreement on the CI-CS scores by consensus. If consensus cannot be achieved, then the average score will be taken. All disagreements will be documented.
    The statistical analysis of this endpoint will utilize a single sample t-test comparing the mean value of the primary endpoint with zero. This endpoint allows the effect N-Acetyl-L-Leucine to be measured both in terms of improvement during treatment followed by any deterioration once treatment is removed.
    Summary statistics will in addition be calculated separately according to subgroups defined by the chosen anchor test
    El criterio principal de valoración para el estudio se basa en la comparación de la impresión clínica del cambio en la gravedad (CI-CS) de los evaluadores a los que se oculta el tratamiento mediante la comparación de vídeos que muestran el cambio del rendimiento en el paciente después de 6 semanas en una escala de síntomas clínicos principal definida previamente: o bien la prueba del clavijero con nueve orificios de la mano dominante (PC9O-MD) o la prueba de marcha de 8 metros (PM8M).
    La comparación del vídeo de la visita 4 con el de la visita 2 y la comparación del vídeo de la visita 6 con el de la 4 proporcionarán las puntuaciones que contribuyan a generar el criterio principal de valoración. Cada una de estas comparaciones puntuará el cambio en una escala de Likert de 7 puntos (de +3 = mejora significativa a -3 = empeoramiento significativo).
    Durante el tratamiento previo, el médico responsable evaluará todos los síntomas clínicos del paciente y seleccionará, en la visita 1, una de las dos pruebas (PC9O-MD o PM8M) como herramienta principal sobre la que basar la evaluación de CI-CS. Se llevará a cabo una evaluación cognitiva durante la visita 1 de acuerdo con los procedimientos estándar del centro clínico y con objeto de realizar la selección de la prueba funcional principal apropiada para cada paciente desde un punto de vista motor y cognitivo.
    La evaluación primaria de la CI-CS será realizada por dos neurólogos independientes cuyos exámenes se basarán en los vídeos de la prueba principal que se realizarán en cada visita. A estos evaluadores se les ocultarán los períodos de tratamiento (valoración inicial, tratamiento o reposo farmacológico) para reducir el sesgo de detección y procedimiento.
    El criterio principal de valoración se define como la comparación de la CI-CS del fin del tratamiento con N-acetil-L-leucina (visita 4) con la valoración inicial (visita 2) menos la comparación de la CI-CS del final del período de reposo farmacológico (visita 6) con el final del tratamiento con N-acetil-L-leucina (visita 4).
    El evaluador a quien se oculta el tratamiento recibirá instrucciones mediante la evaluación de CI-CS que se examinará: «teniendo presente el primer vídeo, ¿qué nivel de gravedad ha alcanzado el rendimiento del paciente en las pruebas PC9O-MD o PM8M (ha mejorado o ha empeorado) en las 6 semanas, tal y como se observa en el segundo vídeo?».
    La idea es que los observadores a quienes se oculta la información alcancen por consenso un acuerdo en las puntuaciones de CI-CS. Si no se consigue este consenso, se tomará la puntuación media. Se deben documentar todos los desacuerdos.
    El análisis estadístico de este criterio de valoración utilizará una prueba t de Student de muestra única que compare el valor medio del criterio principal de valoración con cero. Este criterio de valoración permite que se mida el efecto de la N-acetil-L-leucina tanto en términos de mejora durante el tratamiento como de deterioro una vez se ha dejado el tratamiento.
    Además, las estadísticas de resumen se calcularán por separado según los subgrupos definidos por la prueba elegida como herramienta.
    E.5.1.1Timepoint(s) of evaluation of this end point
    CI-CS comparing Baseline (Day 1) with IB1001 verses the end of 6-weeks treatment with IB1001 (Approximately Day 42) MINUS the CI-CS comparing the end of 6-weeks treatment with IB1001 (Approximately Day 42) verses the end of 6-weeks post-treatment washout (Approximately day 84)
    Comparación de la CI-CS basal (Día 1) con IB1001 versus el fin del tratamiento de 6 semanas con IB1001 (aproximadamente día 42) MENOS la comparación de la CI-CS del fin del tratamiento de 6 semanas con IB1001 (aproximadamente día 42) versus el fin del reposo farmacológico posterior al tratamiento de 6 semanas (aproximadamente el día 84)
    E.5.2Secondary end point(s)
    •Spinocerebellar Ataxia Functional Index (SCAFI)
    •Scale for Assessment and Rating of Ataxia (SARA) score
    •Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y for patients aged <18 years (visual analogue scale; descriptive system)
    •Modified Disability Rating Scale (mDRS)
    •Treating Physician Clinical Global Impression of Severity (CGI-S) at every visit
    •Treating Physician Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4)
    •Caregiver Clinical Global Impression of Severity (CGI-S) at every visit
    •Caregiver Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4)
    •Patient Clinical Global Impression Scales Impression of Severity (CGI-S) at every visit if they are able
    •Patient Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4) if they are able
    •Índice funcional de ataxia espinocerebelosa (SCAFI)
    •Puntuación de la escala para evaluación y calificación de la ataxia (SARA)
    •Cuestionario EQ-5D-5L de calidad de vida para pacientes de 18 años o más, EQ-5D-Y para niños menores de 18 años (escala analógica visual, sistema descriptivo)
    •Escala de valoración de la discapacidad modificada (mDRS, de sus siglas en inglés)
    •Impresión global clínica de la gravedad (CGI-S) por parte del médico del responsable en cada visita
    •Comparación de la impresión global clínica del cambio (CGI-C) por parte del médico responsable del final del tratamiento (visita 4) con la valoración inicial (visita 2), y del final del reposo farmacológico (visita 6) con el final del tratamiento (visita 4)
    •Impresión global clínica de la gravedad (CGI-S) por parte del cuidador en cada visita
    •Comparación de la impresión global clínica del cambio (CGI-C) por parte del cuidador del final del tratamiento (visita 4) respecto a la valoración inicial (visita 2), y del final del reposo farmacológico (visita 6) con el final del tratamiento (visita 4)
    •Impresión global clínica de la gravedad (CGI-S) por parte del paciente en cada visita, si es capaz
    •Comparación de la impresión global clínica del cambio (CGI-C) por parte del paciente del final del tratamiento (visita 4) con respecto a la valoración inicial (visita 2), y del final del reposo farmacológico (visita 6) con el final del tratamiento (visita 4), si es capaz
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84)
    Basal (Día 1) hasta el final del tratamiento con IB1001 (aproximadamente el Día 42); Fin del tratamiento con IB1001
    (aproximadamente el día 42) hasta el fin del reposo farmacológico posterior al tratamiento (aproximadamente el día 84)
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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
    United Kingdom
    United States
    E.8.7Trial 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
    A patient is considered to have completed the study if he/she has completed all phases of the study including the last visit.

    The end of the study is defined as the date of the last visit of the last patient in the study globally.
    Se considera que un paciente ha completado el estudio si ha completado todas las fases del estudio, incluida la última visita.

    El final del estudio se define como la fecha de la última visita del último paciente en el estudio a nivel mundial.
    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
    E.8.9.2In all countries concerned by the trial years1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 15
    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) Yes
    F. of subjects for this age range: 4
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 11
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 24
    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 Yes
    F. of subjects incapable of giving consent
    Signed consent required by patient and/or their legal representative/ parent
    Consentimiento firmado requerido por el paciente y / o su representante legal / padre/Madre
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 39
    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)
    Patients who have participated in the study will be offered the opportunity to participate in a planned rollover, open-label study if the safety and tolerability during the 6-week treatment are considered to be acceptable by the Investigator for each specific patient, and the Investigator determines further treatment with IB1001 to be in the patient’s interest. This rollover study will allow patients to have further access to IB1001 for one year.
    A los pacientes que hayan participado en el estudio se les ofrecerá la oportunidad de participar en un estudio de extensión abierto, si el investigador considera que la seguridad y la tolerabilidad durante el tratamiento de 6 semanas son aceptables para cada paciente específico, y el investigador determina que el tratamiento adicional con IB1001 es para el interés del paciente. Este estudio de extensión permitirá a los pacientes tener acceso a IB1001 durante un año.
    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 Decision2019-06-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-01-09
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