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    Summary
    EudraCT Number:2021-006794-37
    Sponsor's Protocol Code Number:VRDN-001-101
    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:2023-02-02
    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 number2021-006794-37
    A.3Full title of the trial
    A multiple ascending dose (MAD) safety, tolerability and efficacy study of VRDN-001, a humanized monoclonal antibody directed against the IGF-1 receptor, in normal healthy volunteers (NHVs) and subjects with thyroid eye disease (TED)
    Estudio de dosis múltiples ascendentes (DMA) para evaluar la seguridad, la tolerabilidad y la eficacia de VRDN-001, un anticuerpo monoclonal humanizado dirigido contra el receptor de IGF-1, en voluntarios sanos normales (VSN) y pacientes con oftalmopatía tiroidea (OT)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Safety, Tolerability and Efficacy Study of VRDN 001
    Estudio de Seguridad, Tolerabilidad y eficacia de VRDN-001
    A.3.2Name or abbreviated title of the trial where available
    A Safety, Tolerability and Efficacy Study of VRDN 001
    Estudio de seguridad, tolerabilidad y eficacia de VRDN 001
    A.4.1Sponsor's protocol code numberVRDN-001-101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05176639
    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 SponsorViridian Therapeutics, 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 supportViridian Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationViridian Therapeutics, Inc.
    B.5.2Functional name of contact pointViridian Clinical Trials Desk
    B.5.3 Address:
    B.5.3.1Street Address221 Crescent Street, Suite 401
    B.5.3.2Town/ cityWaltham
    B.5.3.3Post codeMA 02453
    B.5.3.4CountryUnited States
    B.5.6E-mailviridianclinicaltrials@viridiantherapeutics.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 nameVRDN-001
    D.3.2Product code VRDN-001
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNn/a
    D.3.9.1CAS number 2728655-31-8
    D.3.9.2Current sponsor codeVRDN-001
    D.3.9.3Other descriptive nameInsulin-like growth factor-1 receptor (IGF-1R) inhibitor
    D.3.9.4EV Substance CodeSUB265864
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 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 placeboSolution for injection/infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Thyroid eye disease (TED)
    Oftalmopatía tiroidea (OT)
    E.1.1.1Medical condition in easily understood language
    Thyroid eye disease (TED)
    Oftalmopatía tiroidea (OT)
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10084358
    E.1.2Term Thyroid eye disease
    E.1.2System Organ Class 100000004853
    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 safety, tolerability, and efficacy of VRDN-001, and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of VRDN-001 in NHV and TED patients over a dose range of 3.0 to 20.0 mg/kg.
    Establecer la seguridad, la tolerabilidad y la eficacia de VRDN-001, así como los perfiles farmacocinéticos (FC) y farmacodinámicos (FD) de VRDN-001 en VSN y pacientes con OT en un intervalo de dosis de 3,0 a 20,0 mg/kg.
    E.2.2Secondary objectives of the trial
    Not applicable
    No applica
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Active and Chronic TED MAD subjects:
    1.Be able to understand the study procedures and the risks involved and be willing to provide written informed consent before the first study-related activity
    2.Be an adult male or female subject, at least 18 years of age or older
    3.Have had a clinical diagnosis of Graves’ disease associated with active TED with a CAS of ≥4 on the 7-item scale for the study eye OR have had a clinical diagnosis of Graves’ disease associated with chronic TED and where there will be no CAS requirement
    4.Have moderate to severe (an appreciable impact on daily living) TED associated with at least one of the following: lid retraction of ≥2 mm, moderate or severe soft tissue involvement, proptosis of ≥3 mm above normal values for race and gender, and/or periodic or constant diplopia)
    5.Have documented evidence of ocular symptoms or signs associated with active TED that began within 1 year prior to study screening OR have documented evidence of ocular symptoms or signs associated with chronic TED that began >1 year
    6.Be euthyroid, or with only mild hyper- or hypothyroidism defined as free thyroxine (FT4) and free triiodothyronine (FT3) levels <50% above or below the normal limits at screening. Every effort must be made to correct any mild hypo- or hyperthyroidism promptly and maintain a euthyroid state for the entire duration of the study. Thyroidectomy, radioactive iodine (RAI) treatment, or orbital decompression surgery limited to bone (no excision of fat) are NOT exclusions
    7.Not require immediate surgical ophthalmological intervention in the study eye for any reason
    8.Have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels <3 in times the upper limit of normal (ULN) or serum creatinine <1.5 times the ULN for their age and diabetic subjects must have a glycated hemoglobin (HbA1c) of <8.5% with no new diabetic medication (oral or insulin) commenced within the previous 12 weeks, or have had more than a 10% change in the dose of a currently prescribed diabetic medication within the previous 12 weeks
    9.Have a negative serum pregnancy test at screening and further negative urine tests immediately before each dose of study medication and other applicable visits following the last dose of study medication as described in Appendices 1B and 1C
    10. Be surgically sterile males for at least 6 weeks, or agree to use an acceptable method of contraception such as a condom and a second highly effective contraception from Screening up to and including 100 days after the last dose of study medication
    11.Be willing and able to comply with all the requirements of the protocol for the entire duration of the study
    Active TED Extension subjects
    Subjects must:
    1.Be able to understand the study procedures and the risks involved and be willing to provide written informed consent before the first study-related activity
    2. Be an adult male or female subject, at least 18 years of age or older
    3. Have had a clinical diagnosis of Graves’ disease associated with active TED with a CAS of ≥ 4 on the 7-item scale for the study eye
    4. Have moderate to severe (i.e., has an appreciable impact on daily living) active TED associated with proptosis of ≥3 mm above normal values for race and gender and at least one of the following: lid retraction of ≥2 mm, moderate or severe soft tissue involvement, periodic or constant diplopia, spontaneous retrobulbar pain or pain on eye movement, swelling of the conjunctiva, eyelids or plica, or redness of the eyelids or plica
    5. Have documented evidence of ocular symptoms or signs associated with active TED that began within 15 months prior to study screening
    6. VRDN- 001 can be started concomitantly with attempts to achieve euthyroid status. Underlying thyroid status is not an inclusion criterion. Thyroidectomy, radioactive iodine (RAI) treatment, or orbital decompression surgery limited to bone (no excision of fat) are NOT exclusions
    7. Not require expected immediate surgical ophthalmological or orbital surgery in the study eye for any reason
    8. VRDN- 001 can be used with caution in patients with diabetes mellitus. Diabetic subjects should be monitored by their endocrinologist and have at study entry a glycated hemoglobin (HbA1c) of <8.5%
    9. Have a negative serum pregnancy test at screening and further negative urine tests immediately before each dose of study medication following the last dose of study medication as described in Appendix 1
    10. Be surgically sterile males for at least 6 weeks, or agree to use an acceptable method of contraception such as a condom and a second highly effective method of contraception as described in Section 4.4 from Screening up to and including 100 days after the last dose of study medication
    11. Be willing and able to comply with all the requirements of the protocol for the entire duration of the study
    Sujetos con OT activa y crónica de los grupos de DMA:
    1.Estar dispuestos y entender los procedimientos del estudio y riesgos y proporcionar el consentimiento informado por escrito antes de comenzarel estudio
    2.Ser un adulto, hombre o mujer, ≥18 años
    3.Haber sido diagnosticado de enferm de Graves asociada a OT activa con una CAS de ≥ 4 en la escala de 7 ítems para el ojo del estudio o haber recibido un diagnóstico de enferm de Graves asociada a OT crónica, en cuyo caso no habrá requisitos para la CAS
    4.Tener OT de moderada a grave (un impacto apreciable en la vida) asociada con al menos uno de los siguientes: retracción palpebral de ≥2 mm, afectación moderada o grave de partes blandas, proptosis de ≥3 mm por encima de los valores normales para la raza y género, y/o diplopía periódica o constante)
    5.Tener evidencia documentada de síntomas o signos oculares asociados a OT activa que empezaron al menos 1 año antes de la selección o evidencia documentada de síntomas o signos oculares asociados con OT crónica que empezaron >1 año antes
    6.Ser eutiroideos, o solo con hiper o hipotiroidismo leve definido como niveles de tiroxina libre y triyodotironina libre <50 % fuera la normalidad. Intentar corregir rápidamente cualquier hipo o hipertiroidismo leve y mantener un estado eutiroideo durante el estudio. La tiroidectomía, el tratamiento con yodo radioactivo o cirugía de descompresión orbitaria limitada al hueso (sin escisión de grasa) NO son criterios de exclusión
    7.No requerir intervención quirúrgica oftalmológica inmediata en el ojo del estudio por cualquier motivo
    8.Tener niveles de alanina aminotransferasa o aspartato aminotransferasa <3 veces el límite superior de la normalidad o creatinina sérica <1,5 veces el LSN para su edad; los diabéticos deben tener unos niveles de hemoglobina glicosilada <8,5 % sin nuevos medicamentos para la diabetes (orales o insulina) iniciados en las últimas 12 semanas, o haber tenido un cambio de más del 10 % en la dosis de una medicación prescrita actualmente para la diabetes en las 12 semanas previas
    9.Tener una prueba de embarazo en suero negativa en la selección y pruebas adicionales de embarazo en orina negativas justo antes de cada dosis y el resto de visitas aplicables después de la última dosis como se describe en los Apéndices 1B y 1C
    10.Ser varones esterilizados quirúrgicamente durante al menos 6 semanas, o estar de acuerdo en usar un método anticonceptivo aceptable, como un preservativo y un segundo método muy eficaz, desde la selección hasta 100 días tras de la última dosis
    11.Estar dispuestos y ser capaces de cumplir con todos los requisitos del protocolo a lo largo de todo el estudio

    Sujetos con OT activa de las cohortes de extensión:
    1.poder entender los procedimientos del estudio y riesgos y estar dispuestos a proporcionar el consentimiento informado por escrito antes de comenzar el estudio
    2.Ser un adulto, hombre o mujer, de al menos 18 años
    3.Haber sido diagnosticado de enferm de Graves asociada a OT activa con una CAS de ≥4 en la escala de 7 ítems para el ojo del estudio
    4.Tener OT de moderada a grave (es decir, tiene un impacto apreciable en la vida) asociada con proptosis de ≥3 mm por encima de valores normales para la raza y sexo y al menos uno de los siguientes: retracción palpebral de ≥2 mm, afectación moderada o grave de partes blandas, diplopía periódica o constante, dolor retrobulbar espontáneo o dolor al mover los ojos, hinchazón de conjuntiva, párpados o pliegues, o enrojecimiento de los párpados o pliegues
    5.Tener evidencia documentada de síntomas o signos oculares asociados a OT activa que empezaron en el plazo de 15 meses antes de la selección
    6.VRDN-001 se puede iniciar de forma concomitante con los intentos de lograr el estado eutiroideo. El estado subyacente de la tiroides no es un criterio de inclusión. La tiroidectomía, el tratamiento con yodo radioactivo o la cirugía de descompresión orbitaria limitada al hueso (sin escisión de grasa) NO son criterios de exclusión
    7.No requerir cirugía quirúrgica oftalmológica u orbitaria inmediata en el ojo del estudio por cualquier motivo
    8.VRDN-001 se puede utilizar con precaución en pacientes con diabetes mellitus. Los diabéticos deben ser supervisados por su endocrinólogo y tener al iniciar el estudio un nivel de hemoglobina glicosilada de <8,5 %
    9.Tener una prueba de embarazo en suero negativa en la selección y pruebas adicionales de embarazo en orina negativas justo antes de cada dosis y después de la última dosis como se describe en el Apéndice
    10.Ser varones esterilizados quirúrgicamente durante al menos 6 semanas, o estar de acuerdo en usar un método anticonceptivo aceptable, como un preservativo y un segundo método muy eficaz, como se describe en la Sección 4.4 desde la selección hasta 100 días (inclusive) tras de la última dosis
    11.Estar dispuestos y ser capaces de cumplir con todos los requisitos del protocolo a lo largo del estudio
    E.4Principal exclusion criteria
    Active and Chronic TED MAD Subjects:
    1.Have received prior treatment with another anti-IGF-1R mAb or any investigational agent for TED
    2.Have decreased visual acuity (VA) in the study eye, defined as ≥2 Snellen lines or equivalent, due to optic neuropathy, new visual field defect, or color defect secondary to optic nerve involvement within previous 6 months
    3.Have corneal decompensation in the study eye unresponsive to medical management
    4.Have a decrease in CAS of ≥2 points between screening assessment and Day -1 for active TED subjects only
    5.Have a decrease in proptosis of ≥2 mm in the study eye between screening assessment and Day -1
    6.Have had previous orbital irradiation or surgery in the study eye for TED
    7.Have known history of clinically significant ear pathology, ear surgery or hearing impairment
    8.Have inflammatory bowel disease (e.g. biopsy proven or clinical evidence of inflammatory bowel disease).
    9.Have used systemic corticosteroids for any condition, including TED, within 4 weeks prior to the first dose of study medication (topical is permitted)
    10.Have received rituximab, or tocilizumab, or other immunosuppressive agent within 90 days prior to the first dose of study medication
    11.Have received an investigational agent for any condition within 60 days
    12.Have a pre-existing ophthalmic condition in the study eye, which in the opinion of the Investigator, would confound interpretation of the study results
    13.Be a pregnant or lactating woman
    14.Be an active alcoholic or illicit drug user or considered at high risk of relapse by the Investigator
    15.Have a known hypersensitivity to any of the components of VRDN-001 or placebo formulations, or prior hypersensitivity to monoclonal antibodies (mAbs)
    16.Have any condition, which in the opinion of the Investigator, would preclude inclusion in the study
    17.Have a positive test to human immunodeficiency virus (HIV-1 and HIV-2)
    18.Have a positive test for active hepatitis B or hepatitis C infection
    19.Have previously participated in this study or any study of VRDN-001
    Active TED Extension subjects
    Subjects must not:
    1. Have received prior treatment with another anti-IGF-1R mAb or any investigational agent for TED
    2. Have a compressive optic neuropathy of TED that is expected to require surgical decompression in the immediate future.
    3. Have corneal decompensation in the study eye unresponsive to medical management
    4. Have a decrease in CAS of ≥2 points between screening assessment and Day -1
    5. Have a decrease in proptosis of ≥2 mm in the study eye between screening assessment and Day -1
    6. Have had previous orbital irradiation for TED to the study eye’s orbit
    7. Have known history of clinically significant ear pathology, ear surgery or hearing impairment
    8. Have inflammatory bowel disease (e.g., biopsy proven or clinical evidence of inflammatory bowel disease)
    9. Have used systemic corticosteroids for any condition, including TED, within 2 weeks prior to the first dose of study medication (topical is permitted)
    10. Have received rituximab, or tocilizumab, or other immunosuppressive agent within 60 days prior to the first dose of study medication
    11. Have received an investigational agent for any condition within 60 days
    12. Have a pre-existing ophthalmic condition in the study eye which in the opinion of the Investigator, would confound interpretation of the study results
    13. Be a pregnant or lactating woman
    14. Be an active alcoholic or illicit drug user or considered at high risk of relapse by the Investigator
    15. Have a known hypersensitivity to any of the components of VRDN-001 or placebo formulations, or prior hypersensitivity to monoclonal antibodies (mAbs)
    16. Have any condition, which in the opinion of the Investigator, would preclude inclusion in the study
    17. Have a positive test for human immunodeficiency virus (HIV-1 and HIV-2)
    18. Have a positive test for active hepatitis B or hepatitis C infection
    19. Have previously participated in this study or any study of VRDN-001
    Sujetos con OT activa y crónica de los grupos de DMA:
    1.Haber recibido tratamiento previo con otro mAb anti-IGF-1R o cualquier fármaco en fase de investigación para la OT.
    2.Tener una disminución de la agudeza visual (AV) en el ojo del estudio, definida como ≥2 líneas de Snellen o equivalente, debido a neuropatía óptica, nuevo defecto del campo visual o defecto de color secundario a la afectación del nervio óptico en los últimos 6 meses.
    3.Tener descompensación corneal en el ojo del estudio que no responde al tratamiento médico.
    4.Tener una disminución en la CAS de ≥2 puntos entre la evaluación de la selección y el día -1, para los sujetos con OT activa solamente.
    5.Tener una disminución de la proptosis de ≥2 mm en el ojo del estudio entre la evaluación de la selección y el día -1.
    6.Haberse sometido a irradiación orbital previa o cirugía en el ojo del estudio para la OT.
    7.Tener antecedentes conocidos de enfermedad del oído clínicamente significativa, cirugía del oído o trastorno auditivo.
    8.Tener enfermedad inflamatoria intestinal (p. ej., evidencia clínica o comprobada por biopsia de enfermedad inflamatoria intestinal).
    9.Haber usado corticosteroides sistémicos para cualquier afección, incluida la OT, en las 4 semanas anteriores a la primera dosis de la medicación del estudio (se permite el uso tópico).
    10.Haber recibido rituximab, tocilizumab u otro agente inmunosupresor en los 90 días anteriores a la primera dosis del medicamento del estudio.
    11.Haber recibido un fármaco en fase de investigación para cualquier afección en los últimos 60 días.
    12.Tener una afección oftálmica preexistente en el ojo del estudio que, en opinión del investigador, podría confundir la interpretación de los resultados del estudio.
    13.Ser mujer y estar embarazada o en periodo de lactancia.
    14.Ser consumidor activo de alcohol o drogas o ser considerado un sujeto con alto riesgo de recaída por el investigador.
    15.Tener una hipersensibilidad conocida a cualquiera de los componentes de las formulaciones de VRDN-001 o el placebo, o hipersensibilidad previa a los anticuerpos monoclonales (mAbs).
    16.Tener cualquier afección que, en opinión del investigador, impediría la inclusión en el estudio.
    17.Tener una prueba positiva para el virus de la inmunodeficiencia humana (VIH-1 y VIH-2)
    18.Tener una prueba positiva para la infección activa por el virus de la hepatitis B o hepatitis C
    19.Haber participado previamente en este estudio o en cualquier estudio de VRDN-001
    Sujetos con OT activa de las cohortes de extensión
    Los sujetos no deben:
    1.Haber recibido tratamiento previo con otro mAb anti-IGF-1R o cualquier fármaco en fase de investigación para la OT.
    2.Tener una neuropatía óptica compresiva debido a la OT que se espera que requiera cirugía de descompresión en el futuro inmediato.
    3.Tener descompensación corneal en el ojo del estudio que no responde al tratamiento médico.
    4.Tener una disminución en la CAS de ≥2 puntos entre la evaluación de la selección y el día -1.
    5.Tener una disminución de la proptosis de ≥2 mm en el ojo del estudio entre la evaluación de la selección y el día -1.
    6.Haberse sometido irradiación orbital previa para la OT en la órbita del ojo del estudio.
    7.Tener antecedentes conocidos de enfermedad del oído clínicamente significativa, cirugía del oído o trastorno auditivo.
    8.Tener enfermedad inflamatoria intestinal (p. ej., evidencia clínica o comprobada por biopsia de enfermedad inflamatoria intestinal).
    9.Haber usado corticosteroides sistémicos para cualquier afección, incluida la OT, en las 2 semanas anteriores a la primera dosis de la medicación del estudio (se permite el uso tópico).
    10.Haber recibido rituximab, tocilizumab u otro agente inmunosupresor en los 60 días anteriores a la primera dosis del medicamento del estudio.
    11.Haber recibido un fármaco en fase de investigación para cualquier afección en los últimos 60 días.
    12.Tener una afección oftálmica preexistente en el ojo del estudio que, en opinión del investigador, podría confundir la interpretación de los resultados del estudio.
    13.Ser mujer y estar embarazada o en periodo de lactancia.
    14.Ser consumidor activo de alcohol o drogas o ser considerado un sujeto con alto riesgo de recaída por el investigador.
    15.Tener una hipersensibilidad conocida a cualquiera de los componentes de las formulaciones de VRDN-001 o el placebo, o hipersensibilidad previa a los anticuerpos monoclonales (mAbs).
    16.Tener cualquier afección que, en opinión del investigador, impediría la inclusión en el estudio.
    17.Tener una prueba positiva para el virus de la inmunodeficiencia humana (VIH-1 y VIH-2)
    18.Tener una prueba positiva para la infección activa por el virus de la hepatitis B o hepatitis C
    19.Haber participado previamente en este estudio o en cualquier estudio de VRDN-001
    E.5 End points
    E.5.1Primary end point(s)
    SAFETY ENDPOINTS:
    Adverse Events (AEs), Serious Adverse Events (SAEs) and Laboratory Assessments will be monitored and recorded throughout the duration of the study.
    PRIMARY EFFICACY ENDPOINT IN THE USA AND CANADA IN THE EXTENSION STUDY
    Proptosis Responder Rate in the study (more proptotic) eye (i.e., reduction of proptosis of ≥ 2 mm from baseline [without a corresponding increase of ≥ 2 mm in the fellow eye] as measured by exophthalmometer) at 24 weeks
    PRIMARY EFFICACY ENDPOINT IN AUSTRALIA, EU AND UK IN THE EXTENSION STUDY
    Overall Response Rate comprised of Proptosis Responder Rate in the study (more proptotic) eye (i.e., reduction of proptosis of ≥ 2 mm from baseline [without a corresponding increase of ≥ 2 mm in the fellow eye] as measured by exophthalmometer) at 24 weeks and Clinical Activity Responder Rate in the study eye (i.e., reduction in CAS ≥ 2 points from baseline [without a corresponding increase of ≥ 2 points in the fellow eye]) at 24 weeks
    Criterios de valoración de la seguridad:
    •Los acontecimientos adversos (AA), los acontecimientos adversos graves (AAG) y las evaluaciones analíticas se supervisarán y registrarán durante todo el estudio
    Criterio principal de valoración de la eficacia en EE. UU. y Canadá en el estudio de extensión:
    •Índice de respuesta a la proptosis en el ojo del estudio (más proptótico) (es decir, reducción de la proptosis de ≥ 2 mm desde el valor inicial [sin un aumento correspondiente de ≥ 2 mm en el ojo contralateral] medido mediante exoftalmómetro) a las 24 semanas
    Criterio principal de valoración de la eficacia en Australia, la UE y el Reino Unido en el estudio de extensión:
    •Tasa de respuesta general, compuesta por la tasa de respuesta de la proptosis en el ojo del estudio (ojo más proptótico) (es decir, reducción en la proptosis de≥ 2 mm desde el valor inicial [sin un aumento correspondiente de ≥ 2 mm en el ojo contralateral] medido con un exoftalmómetro) a las 24 semanas y tasa de respuesta a la actividad clínica en el ojo del estudio (es decir, una reducción en CAS de ≥ 2 puntos desde el valor inicial [sin un aumento correspondiente de ≥ 2 puntos en el ojo contralateral]) a las 24 semanas
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the duration of the study
    At 24 weeks in the USA & Canada and in Australia, EU and UK extension studies
    A lo largo de la duración del estudio
    A las 24 semanas en EE. UU. y Canadá y en Australia, estudios de extensión en la UE y el Reino Unido
    E.5.2Secondary end point(s)
    SECONDARY EFFICACY ENDPOINTS:
    Proptosis Responder Rate in the study eye (i.e., reduction of proptosis of ≥ 2 mm from baseline [without a corresponding increase of ≥ 2 mm in the fellow eye] as measured by exophthalmometer) at 6 and 12 weeks in the MAD study and at 52 weeks in the extension cohorts.
    Proptosis Responder Rate in the fellow eye (i.e., reduction of proptosis of ≥ 2 mm from baseline as measured by exophthalmometer) at 6 and 12 weeks in the MAD study and 24 and 52 weeks in the extension cohorts
    Proptosis Responder Rate in the study eye (i.e., reduction of proptosis of ≥ 2 mm from baseline [without a corresponding increase of ≥ 2 mm in the fellow eye] as measured by magnetic resonance imaging [MRI]) at 6 and 12 weeks in the MAD study, and 24 and 52 weeks in the extension cohorts.
    Proptosis Responder Rate in the fellow eye (i.e., reduction of proptosis of ≥ 2 mm from baseline as measured by MRI) at 6 and 12 weeks in the MAD study, and 24 and 52 weeks in the extension cohorts
    Clinical Activity Responder Rate in the study eye (i.e., reduction in CAS ≥ 2 points from baseline [without a corresponding increase of ≥ 2 points in the fellow eye]) at 6 and 12 weeks in the MAD study, and 24 (US and Canada) and 52 weeks in the extension cohorts
    Clinical Activity Responder Rate in the fellow eye (i.e., reduction in CAS ≥ 2 points from baseline) at 6 and 12 weeks in the MAD study, and 24 (US and Canada) and 52 weeks in the extension cohorts
    Change from Baseline within the study and fellow eyes independently at 6 and 12 weeks in the MAD study, and 24 and 52 weeks in the extension cohorts in the following:
    • Change in measurement of proptosis by MRI
    • Change in measurement of proptosis by exophthalmometer
    • Change in volume of orbital fat as determined by MRI
    • Change in volume of extraocular muscles as determined by MRI
    • Change in facial fat volume as determined by MRI
    • Change in digital measurement of eye color
    • Change in digital and manual measurement of lid retraction
    • Change in clinical activity score (CAS)
    • Change in subjective diplopia score
    • Change in Graves’ Orbitopathy-Quality of Life (GO-QoL) combined score
    • Change in GO-QoL activity subscale
    • Change in GO-QoL appearance subscale
    • Change in Snellen visual acuity (VA)
    Criterios de valoración secundaria:
    •Tasa de respuesta de la proptosis en el ojo del estudio (es decir, reducción en la proptosis de ≥ 2 mm desde el valor inicial [sin un aumento correspondiente de ≥ 2 mm en el ojo contralateral] medido con un exoftalmómetro) a las 6 y 12 semanas en el estudio de DMA y a las 52 semanas en las cohortes de extensión
    •Tasa de respuesta de la proptosis en el ojo contralateral (es decir, reducción en la proptosis de ≥ 2 mm desde el valor inicial, medido con un exoftalmómetro) a las 6 y 12 semanas en el estudio de DMA y a las 24 y 52 semanas en las cohortes de extensión
    •Tasa de respuesta de la proptosis en el ojo del estudio (es decir, reducción en la proptosis de ≥ 2 mm desde el valor inicial [sin un aumento correspondiente de ≥ 2 mm en el contralateral otro] medido por resonancia magnética [RM]) a las 6 y 12 semanas en el estudio de DMA y a las 24 y 52 semanas en las cohortes de extensión
    •Tasa de respuesta de la proptosis en el ojo contralateral (es decir, reducción en la proptosis de ≥ 2 mm desde el valor inicial medido por RM) a las 6 y 12 semanas en el estudio de DMA y a las 24 y 52 semanas en las cohortes de extensión
    •Tasa de respuesta de la actividad clínica en el ojo del estudio (es decir, reducción en CAS ≥ 2 puntos desde el valor inicial [sin un aumento correspondiente de ≥ 2 puntos en el ojo contralateral]) a las 6 y 12 semanas en el estudio de DMA, y a las 24 (EE. UU. y Canadá) y 52 semanas en las cohortes de extensión
    •Tasa de respuesta de la actividad clínica en el ojo contralateral (es decir, reducción en CAS ≥ 2 puntos desde el inicio) a las 6 y 12 semanas en el estudio de DMA, y 24 (EE. UU. y Canadá) y 52 semanas en las cohortes de extensión

    Cambio desde el inicio en el ojo del estudio y el ojo contralateral de forma independiente a las 6 y 12 semanas en el estudio de DMA y a las 24 y 52 semanas en las cohortes de extensión en lo siguiente:
    •Cambio en la medición de la proptosis por RM
    •Cambio en la medición de la proptosis por exoftalmómetro
    •Cambio en el volumen de la grasa orbitaria determinado por RM
    •Cambio en el volumen de los músculos extraoculares determinado por RM
    •Cambio en el volumen de grasa facial determinado por RM
    •Cambio en la medición digital del color de ojos
    •Cambio en la medición digital y manual de la retracción del párpado
    •Cambio en la puntuación de actividad clínica (CAS)
    •Cambio en la puntuación de diplopía subjetiva
    •Cambio en la puntuación combinada de orbitopatía de Graves - Calidad de vida
    (GO-QoL)
    •Cambio en la subescala de actividad de GO-QoL
    •Cambio en la subescala de apariencia de GO-QoL
    •Cambio en la agudeza visual (AV) de Snellen
    E.5.2.1Timepoint(s) of evaluation of this end point
    According to the protocol
    Según protocolo
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    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
    Australia
    Canada
    United States
    European Union
    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
    Última visita del último paciente
    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 months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    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: 161
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 23
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 184
    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
    Ninguno
    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 Decision2023-05-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-05-10
    P. End of Trial
    P.End of Trial StatusOngoing
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