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    Summary
    EudraCT Number:2020-005522-28
    Sponsor's Protocol Code Number:ION363-CS1
    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:2023-01-31
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2020-005522-28
    A.3Full title of the trial
    A Phase 1-3 Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION363 in Amyotrophic Lateral Sclerosis Patients with Fused in Sarcoma Mutations (FUS-ALS)
    Estudio de fase 1-3 para evaluar la eficacia, la seguridad, la farmacocinética y la farmacodinámica de ION363 administrado por vía intratecal en pacientes con esclerosis lateral amiotrófica con mutaciones del gen fusionado en sarcoma (ELA-FUS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS).
    Estudio para evaluar la eficacia, la seguridad, la farmacocinética y la farmacodinámica de ION363 en pacientes con esclerosis lateral amiotrófica con mutaciones del gen fusionado en sarcoma (ELA-FUS)
    A.4.1Sponsor's protocol code numberION363-CS1
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04768972
    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 SponsorIonis Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportIonis Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIonis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointIonis Clinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Court
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post codeCA 92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1760-603-2302
    B.5.5Fax number+1760-603-3891
    B.5.6E-mailtbaumann@ionisph.com
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameION363
    D.3.2Product code ION363
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrathecal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot assigned
    D.3.9.1CAS number Not assigned
    D.3.9.2Current sponsor codeION363
    D.3.9.3Other descriptive nameION363 SODIUM
    D.3.9.4EV Substance CodeSUB222715
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 Yes
    D.3.11.13.1Other medicinal product typeAntisense Oligonucleotide
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntrathecal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Amyotrophic Lateral Sclerosis with Fused in Sarcoma mutations
    Esclerosis lateral amiotrófica con mutaciones del gen fusionado en sarcoma
    E.1.1.1Medical condition in easily understood language
    Amyotrophic Lateral Sclerosis
    Amyotrophic Lateral Sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10002026
    E.1.2Term Amyotrophic lateral sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the clinical efficacy of ION363 in clinical functioning and survival in Amyotrophic Lateral Sclerosis (ALS) patients with Fused in Sarcoma mutations (FUS-ALS).
    Evaluar la eficacia clínica de ION363 en cuanto al funcionamiento clínico y la supervivencia en pacientes con esclerosis lateral amiotrófica (ELA) con mutaciones del gen FUS (acrónimo en inglés de «gen fusionado en sarcoma») (ELA-FUS).
    E.2.2Secondary objectives of the trial
    To further evaluate the effects of ION363 in halting, reversing, or slowing the deterioration of clinical functioning and biomarkers of disease severity in FUS-ALS patients.
    Evaluar más a fondo los efectos de ION363 sobre la detención, corrección o ralentización del deterioro del funcionamiento clínico y los biomarcadores de gravedad de la enfermedad en pacientes con ELA-FUS.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria for Part 1:

    1.Signs or symptoms consistent with an ALS disease process in the opinion of the Investigator
    2.Participants in:
    Cohort A must be, at the time of informed consent, 12 – 65 years of age, inclusive, with signs or symptoms consistent with an ALS disease process in the opinion of the Investigator and if 30 to 65 years of age, inclusive, have an ALSFRS-R pre-study slope ≥ 0.4 points per month (calculated as [48-Screening ALSFRS-R score]/time in months since symptom onset)

    Cohort B must be, at the time of informed consent, > 30 years of age, with signs or symptoms consistent with an ALS disease process in the opinion of the Investigator and have an ALSFRS-R pre-study slope < 0.4 points per month (calculated as [48-Screening ALSFRS-R score]/time in months since symptom onset) if between the ages of 30-65, or > 65 years of age with no ALSFRS-R pre-study slope criterion
    3.Confirmed genetic mutation in FUS in a clinical laboratory improvement amendments (CLIA) certified, CE-marked, or equivalent testing laboratory . Mutations must be reviewed and approved by a variant classification committee
    4.Upright (sitting position) slow vital capacity (SVC) as adjusted for sex, age, and height ≥ 50 percentage (%) of predicted value
    5.Participants taking edaravone, riluzole, AMX0035 (sodium phenylbutyrate/taurursodiol combination), sodium phenylbutyrate, or tauroursodeoxycholic acid [TUDCA, also known as taurursodiol or urosodiol]) must be on a stable dose for ≥ 28 days prior to Screening
    6. Females: a) must be non-pregnant and non-lactating and either:
    i. surgically sterile
    ii. post-menopausal
    iii. abstinent*
    or
    iv. if engaged in sexual relations of childbearing potential, agree to use a highly effective contraceptive method from the time of signing the ICF until at least 40 Weeks after the last dose of Study Drug

    b. Males must be abstinent*, surgically sterile (vasectomy with negative semen analysis
    at follow-up, or a surgically sterile non-pregnant female partner) or if engaged in
    sexual relations with a woman of childbearing potential (WOCBP), a highly effective
    contraceptive method must be used (refer to Section 6.3.1) from the time of signing
    the ICF until at least 40 weeks after the last dose of Study Drug
    * Abstinence is only acceptable as true abstinence.




    6.Stable concomitant medications and nutritional support for at least 1 month prior to Study Day 1. Concomitant medications or nutritional support that have not been stable for at least 1 month prior to Study Day 1 may be allowed per Investigator's Judment
    7.Has an informant/caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the participant as to be able to provide accurate information about the participant's cognitive and functional abilities at Screening. Participants < 18 years old at Screening must have a trial partner (parent, caregiver or other) who is reliable, competent and at least 18 years of age, is willing to accompany the participant to trial visits and to be available to the Study Center by phone if needed, and who (in the opinion of the Investigator) is and will remain sufficiently knowledgeable of participant's ongoing condition to respond to Study Center inquiries about the participant

    Inclusion Criteria for Part 2:
    1.Completed, or rescued from, Part 1, Enrolled and received at least 1 dose of ION363 in the Investigator-initiated Study
    2. Satisfy the following:
    a. Females: must be non-pregnant and non-lactating and either:
    i. surgically sterile
    ii. post-menopausal (defined as no menses for 12 months without an alternative
    medical cause. A high follicle stimulating hormone (FSH) level in the
    post-menopausal range may be used to confirm a post-menopausal state in
    women not using hormonal contraception or hormonal replacement therapy.
    However, in the absence of 12 months of amenorrhea, a single FSH
    measurement is insufficient)
    iii. abstinent* or
    iv. if engaged in sexual relations of childbearing potential, agree to use a highly
    effective contraceptive method (refer to Section 6.3.1) from the time of
    signing the ICF until at least 40 weeks after the last dose of Study Drug
    b. Males must be abstinent*, surgically sterile (vasectomy with negative semen
    analysis at follow-up, or a surgically sterile non-pregnant female partner) or if
    engaged in sexual relations with a woman of childbearing potential (WOCBP), a
    highly effective contraceptive method must be used (refer to Section 6.3.1) from
    the time of signing the ICF until at least 40 weeks after the last dose of Study
    Drug
    * Abstinence is only acceptable as true abstinence.
    3.Patient meeting Criteria #1-2 is otherwise suitable for study participation, in the opinion of the Investigator
    Criterios de inclusión correspondientes a la parte 1
    1. Haber otorgado el consentimiento informado por escrito o el asentimiento, si está indicado por la edad del paciente y las normas del centro (firmado y fechado), y las autorizaciones exigidas por la legislación local y ser capaz de cumplir todos los requisitos del estudio.
    2. Los pacientes de:
    a. La cohorte A deben tener entre 12 y 65 años, ambos inclusive, en el momento de obtener el consentimiento informado, así como signos o síntomas compatibles con ELA en opinión del investigador y, en caso de tener entre 30 y 65 años, ambos inclusive, una pendiente en la escala ALSFRS-R antes del estudio ≥0,4 puntos al mes (calculada como [puntuación 48-Screening ALSFRS-R]/tiempo en meses desde el comienzo de los síntomas)
    b. La cohorte B deben tener más de 30 años en el momento de obtener el consentimiento informado, así como signos o síntomas compatibles con ELA en opinión del investigador y una pendiente en la escala ALSFRS-R antes del estudio <0,4 puntos al mes (calculada como [puntuación 48-Screening ALSFRS-R]/tiempo en meses desde el comienzo de los síntomas) en caso de tener entre 30 y 65 años, ambos inclusive, o bien más de 65 años sin necesidad de cumplir ningún criterio relacionado con la pendiente en la escala ALSFRS-R antes del estudio.
    3. Mutación genética confirmada de FUS en un laboratorio de análisis con certificación CLIA, marca CE o equivalente. Las mutaciones deben ser examinadas y aprobadas por un comité de clasificación de variantes.
    4. Capacidad vital lenta (CVL) en posición erguida (sedestación) ajustado respecto a sexo, edad y estatura ≥50% del valor teórico.
    5. Capacidad y disposición para cumplir todos los requisitos del estudio (en opinión del investigador), incluidos desplazamientos al centro del estudio, procedimientos, evaluaciones y visitas.
    6. Los pacientes que estén tomando edaravona, riluzol, AMX0035 (combinación de fenilbutirato sódico/taurursodiol), fenilbutirato sódico o ácido tauroursodesoxicólico (TUDCA, también conocido como taurursodiol o urosodiol) deberán haber recibido una dosis estable durante, como mínimo, los 28 días previos a la selección y estar dispuestos a continuar con esa dosis durante todo el estudio, a menos que el investigador determine que deben suspenderse por motivos médicos, en cuyo caso no podrán reanudarse durante el estudio.
    7. Cumplimiento de lo siguiente:
    a. Mujeres: no deben estar embarazadas ni en período de lactancia y han de presentar una de las circunstancias siguientes:
    i. Haber sido esterilizada quirúrgicamente (p. ej., histerectomía, salpingectomía bilateral, ovariectomía bilateral o vasectomía de la pareja).
    ii. Ser posmenopáusica (definida como toda aquella que lleva 12 meses sin menstruación sin una causa médica alternativa. Podrá utilizarse una concentración elevada de folitropina (FSH) en el intervalo posmenopáusico para confirmar el estado posmenopáusico en las mujeres que no utilicen anticonceptivos hormonales ni tratamiento hormonal sustitutivo. No obstante, en ausencia de 12 meses de amenorrea, resulta insuficiente una sola determinación de FSH).
    iii. Practicar abstinencia*.
    iv. En caso de mantener relaciones sexuales estando en edad fértil, comprometerse a utilizar un método anticonceptivo muy eficaz (véase la Sección 6.3.1 desde el momento de firmar el
    DCI hasta al menos 40 semanas después de la última dosis del fármaco del estudio.
    b. Varones: deberán practicar abstinencia*, haber sido esterilizados quirúrgicamente (vasectomía con espermiograma negativo en el seguimiento o pareja no embarazada y esterilizada quirúrgicamente) o, en caso de mantener relaciones sexuales con una mujer en edad fértil (MEF), utilizar un método anticonceptivo muy eficaz (véase la Sección 6.3.1) desde el momento de firmar el DCI hasta al menos 40 semanas después de la última dosis del fármaco del estudio.
    * La abstinencia solo es aceptable como abstinencia real, es decir, cuando esté en consonancia con el modo de vida preferido y habitual del paciente. La abstinencia periódica (p. ej., métodos del calendario, ovulación, sintotérmico o postovulación), la declaración de abstinencia durante el ensayo y el coito interrumpido no son métodos anticonceptivos aceptables.
    8. Medicación concomitante y apoyo nutricional estables durante al menos un mes antes del día 1 del estudio. A criterio del investigador, podrá permitirse el uso de medicamentos concomitantes o apoyo nutricional que no se hayan mantenido estables durante al menos un mes antes del día 1 del estudio.
    9. Contar con un informador o cuidador que, en opinión del investigador, tenga un contacto frecuente y suficiente con el participante para poder proporcionar información exacta sobre sus capacidades cognitivas y funcionales en la visita de selección.

    Para mas información, por favor, referirse a la sección correspondiente del protocolo del estudio.
    E.4Principal exclusion criteria
    Exclusion Criteria for Part 1:
    1.Requiring permanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days) and/or tracheostomy
    2.Any known ALS-associated mutations except FUS
    3.Positive test result for:
    a.Human immunodeficiency virus (HIV)
    b.Hepatitis C (HCV), unless previously treated and has been serum/plasma HCV RNA negative for at least 6 months after the end of treatment
    c.Hepatitis B (HBV) by HBV surface antigen test, unless currently on nucleotide/nucleoside analogue treatment
    4.Clinically significant (CS) abnormalities in medical history (e.g., previous acute coronary syndrome within 3 months of Screening, major surgery within 2 months of Screening) or physical examination, unless discussed and approved by the Sponsor Medical Monitor
    5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
    6. Uncontrolled hypertension (BP > 160/100 mm Hg)
    7. Malignancy within 1 year of Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 6 months may also be eligible per Investigator judgement
    8. Obstructive hydrocephalus
    9. Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter
    10. Known significant brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment, including tumors or abnormalities by MRI or computed tomography (CT), subarachnoid hemorrhage, suggestion of raised intracranial pressure on MRI or ophthalmic examination, spinal stenosis or curvature, chiari malformation, obstructive hydrocephalus, syringomyelia, tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome
    11. Presence of significant cognitive impairment, not due to a developmental disability, with either a score on the Mini-Mental State Examination (MMSE) < 20 or equivalent assessment, clinical dementia, and unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression, as determined by the Investigator
    12. Concurrent participation in any other interventional clinical study
    13. Previous treatment with an oligonucleotide (including siRNA). This exclusion criterion does not apply to COVID-19 vaccinations, which are allowed.
    14. Treatment with another investigational drug, biological agent, or device, including, but not limited to sodium phenylbutyrate, within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer
    15. History of gene therapy or cell transplantation or any other experimental brain surgery
    16. Antiplatelet or anticoagulant therapy within the 14 days prior to Day 1 or anticipated use during the study, including but not limited to daily, low-dose aspirin (defined as ≤ 150 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban
    17. Clinically significant low platelet count (defined as < 100,000/mm3), coagulation tests, or laboratory abnormalities that would render a patient unsuitable for inclusion
    18. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
    19. Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study
    Criterios de exclusión correspondientes a la parte 1
    1. Necesidad de ventilación permanente (>22 horas de ventilación mecánica [invasiva o no invasiva] al día durante más de 21 días consecutivos) o traqueostomía.
    2. Cualquier mutación conocida asociada a la ELA, excepto de FUS.
    3. Resultado positivo en una prueba de:
    a. Virus de la inmunodeficiencia humana (VIH).
    b. Hepatitis C (VHC), a menos que el paciente haya sido tratado previamente y haya dado negativo para ARN del VHC en suero o plasma durante al menos 6 meses después del final del tratamiento.
    c. Hepatitis B (VHB) según el análisis de antígeno de superficie del VHB, a menos que el paciente esté recibiendo tratamiento con análogos de nucleótidos o nucleósidos.
    4. Anomalías clínicamente significativas en la historia clínica (p. ej., síndrome coronario agudo previo en los 3 meses previos a la selección o intervención de cirugía mayor en los 2 meses previos a la selección) o la exploración física.
    5. Infección activa con necesidad de tratamiento antiviral o antimicrobiano sistémico que no finalizará antes del día 1 del estudio.
    6. Hipertensión no controlada (PA >160/100 mm Hg).
    7. Neoplasia maligna en el año previo a la selección, excepto carcinoma basocelular o espinocelular de piel o carcinoma in situ de cuello uterino tratado con éxito. Los pacientes con antecedentes de otras neoplasias malignas tratadas con intención curativa y que no hayan presentado una recidiva en los seis meses siguientes también podrán participar, a criterio del investigador.
    8. Hidrocefalia obstructiva.
    9. Presencia de una derivación ventriculoperitoneal funcional para drenaje del LCR o de un catéter implantado en el SNC.
    10. Enfermedad cerebral o medular importante conocida que pueda interferir en el proceso de punción lumbar, la circulación del LCR o la evaluación de la seguridad, incluidos tumores o anomalías en la RM o tomografía computarizada (TC), hemorragia subaracnoidea, indicios de hipertensión intracraneal en la RM o exploración oftalmológica, estenosis o curvatura raquídea, malformación de Chiari, hidrocefalia obstructiva, siringomielia, síndrome de la médula espinal anclada y trastornos del tejido conjuntivo, como síndrome de Ehlers-Danlos y síndrome de Marfan.
    11. Presencia de un deterioro cognitivo significativo, no debido a una discapacidad del desarrollo, con una puntuación en el Miniexamen cognoscitivo (MEC) <20 o evaluación equivalente, demencia clínica y enfermedad psiquiátrica inestable, como psicosis, ideación suicida, intento de suicidio o depresión mayor no tratada, según lo determinado por el investigador.
    12. Participación simultánea en cualquier otro estudio clínico intervencionista.
    13. Tratamiento previo con un oligonucleótido (incluido ARNip). Este criterio de exclusión no se aplica a las vacunas contra la COVID-19, cuyo uso está permitido.
    14. Tratamiento con otro fármaco, producto biológico o dispositivo en investigación, entre otros, fenilbutirato sódico, en el mes previo a la selección o el equivalente a 5 semividas del fármaco en investigación, lo que suponga más tiempo.
    15. Antecedentes de terapia génica, trasplante de células o cualquier otro tipo de cirugía cerebral experimental.
    16. Tratamiento con antiagregantes o anticoagulantes en los 14 días previos al día 1 o uso previsto durante el estudio, entre ellos, ácido acetilsalicílico en dosis bajas a diario (definido como ≤150 mg/día), clopidogrel, dipiridamol, warfarina, dabigatrán, rivaroxabán y apixabán.
    17. Recuento bajo de plaquetas (definido como <100 000/mm3), pruebas de coagulación o anomalías analíticas clínicamente significativos que hagan que un paciente no sea apto para participar.
    18. Falta de disposición a cumplir los procedimientos del estudio, incluido el seguimiento, especificados en este protocolo o a cooperar plenamente con el investigador.
    19. Presencia de cualquier otro trastorno que, en opinión del investigador, pueda hacer que el paciente no sea apto para participar o que pueda interferir en su participación o finalización del estudio
    E.5 End points
    E.5.1Primary end point(s)
    Change from Day 1 through Study Day 505 in Part 1 in functional impairment
    Functional impairment to be measured by joint rank analysis of the combined assessment of:
    - In-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score;
    - time of rescue Rescue takes place if there is a deterioration to an ALSFRS-R total score
    of < 15 points AND a decrease of ≥10 points from baseline at Study Day 253, or later, that is confirmed after an interval of at least
    4 weeks. Rescue means the patient may discontinue Part 1 and enter Part 2 of the study;
    - Ventilation Assistance-free survival (VAFS) defined as the time to the earliest occurrence of 1 of the following events:
    a. Death
    b. Permanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days in the absence of an acute reversible event)
    ALSFRS-R measures functional disease severity. The scale measures four functional domains, bulbar function, gross motor skills, fine motor skills, and respiratory. The assessment will contain 12 questions scored from 0 (no function) to 4 (full function), with a total possible score of 48, which will indicate the highest level of function. ALSFRS-R will be a part of the combined assessment of joint rank analysis to assess efficacy in Part 1.
    El criterio de valoración principal será la evaluación de los efectos de ION363, en comparación con placebo, sobre la variación entre el momento basal (es decir, día 1) y el día 505 de la parte 1 del estudio del deterioro funcional, medido mediante una prueba del rango conjunto de la evaluación combinada de lo siguiente:
    • Puntuación ALSFRS-R (Escala de valoración funcional de la esclerosis lateral amiotrófica-revisada) total en el centro.
    • Momento del rescate. El rescate tendrá lugar si se produce un deterioro de la puntuación ALSFRS-R total <15 puntos Y una disminución ≥10 puntos entre el momento basal y el día 253 del estudio, o más tarde, que se confirma tras un intervalo mínimo de 4 semanas. El término «rescate» significa que el paciente podrá abandonar la parte 1 e incorporarse a la parte 2 del estudio.
    • Supervivencia sin ventilación asistida (SSVA), definida como el tiempo transcurrido hasta la primera aparición de uno de los siguientes episodios:
    a. Muerte.
    b. Ventilación permanente (>22 horas de ventilación mecánica [invasiva o no invasiva] al día durante >21 días consecutivos en ausencia de un episodio agudo reversible).

    ALSFRS-R mide la gravedad de la enfermedad funcional. La escala mide cuatro dominios funcionales, función bulbar, habilidades motoras gruesas, habilidades motoras finas y respiratorias. La evaluación contendrá 12 preguntas calificadas de 0 (sin función) a 4 (función completa), con un puntaje total posible de 48, lo que indicará el nivel más alto de función. ALSFRS-R formará parte de la evaluación combinada del análisis de rango conjunto para evaluar la eficacia en la Parte 1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From Baseline to Study Day 505 in Part 1
    Desde el inicio hasta el día de estudio 505 en la parte 1
    E.5.2Secondary end point(s)
    Evaluate the effects of ION363 vs. placebo on change and/or percent change, if appropriate,
    from Baseline to Study Day 505 in Part 1 on clinical assessments and biomarkers of
    disease severity. Specifically, on the following endpoints:
    • Change from Baseline in Amyotrophic Lateral Sclerosis Specific Quality of Life -
    Revised (ALSSQOL-R)
    • Change from Baseline in in-clinic Amyotrophic Lateral Sclerosis Functional Rating
    Scale-Revised (ALSFRS-R)
    • Survival
    • Change from Baseline in in-clinic Slow Vital Capacity (SVC)
    • Change from Baseline in Handheld Dynamometry (HHD)
    • Change from Baseline in Neurofilament light (NfL) concentration in CSF
    Evaluar los efectos de ION363, en comparación con placebo, sobre la variación o la variación porcentual, si procede, entre el momento basal y el día 505 de la parte 1 del estudio de las evaluaciones clínicas y los biomarcadores de gravedad de la enfermedad. Concretamente, de los siguientes criterios de valoración:
    • Variación con respecto al momento basal de la puntuación ALSSQOL-R (Calidad de vida específica de la esclerosis lateral amiotrófica-revisada).
    • Variación con respecto al momento basal de la puntuación ALSFRS-R (Escala de valoración funcional de la esclerosis lateral amiotrófica-revisada) en el centro.
    • Supervivencia.
    • Variación con respecto al momento basal de la capacidad vital lenta (CVL) en el centro.
    •Variación con respecto al momento basal de la dinamometría manual (DM).
    • Variación con respecto al momento basal de la concentración de proteína NfL (cadena ligera de los neurofilamentos) en el LCR
    E.5.2.1Timepoint(s) of evaluation of this end point
    From Baseline to Study Day 505 in Part 1
    Desde el inicio hasta el día de estudio 505 en la parte 1
    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 Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    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 No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Parte 1 doble ciego; Parte 2 y 3 abierto
    Part 1 double blind; Part 2 and Part 3 open label
    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 EEA8
    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
    Brazil
    Canada
    Japan
    Korea, Republic of
    United States
    France
    Poland
    Sweden
    Netherlands
    Spain
    Switzerland
    Germany
    Italy
    Belgium
    Ireland
    Turkey
    United Kingdom
    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
    LVLS
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months1
    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: 17
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 17
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 55
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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.3.3.6.1Details of subjects incapable of giving consent
    Persons of this age group are generally not capable of giving consent.
    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 37
    F.4.2.2In the whole clinical trial 77
    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
    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 Decision2023-12-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-03-22
    P. End of Trial
    P.End of Trial StatusOngoing
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