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    Summary
    EudraCT Number:2019-001237-14
    Sponsor's Protocol Code Number:LIGRADIS
    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:2019-04-30
    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 number2019-001237-14
    A.3Full title of the trial
    Randomized clinical trial, blinded for the researcher and multicenter, to evaluate the efficacy and safety of preoperative preparation with Lugol solution in euthyroid patients with Graves-Basedow disease.
    Ensayo clínico aleatorizado, ciego para el investigador y multicéntrico, para evaluar la eficacia y seguridad de la preparación preoperatoria con solución de Lugol en pacientes eutiroideos con enfermedad de Graves-Basedow.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized clinical trial, blinded for the researcher and multicenter, to evaluate the efficacy and safety of preoperative preparation with Lugol solution in euthyroid patients with Graves-Basedow disease.
    Ensayo clínico aleatorizado, ciego para el investigador y multicéntrico, para evaluar la eficacia y seguridad de la preparación preoperatoria con solución de Lugol en pacientes eutiroideos con enfermedad de Graves-Basedow.
    A.4.1Sponsor's protocol code numberLIGRADIS
    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 SponsorDr. Jesús María Villar del Moral and Dr. José Luis Muñoz de Nova
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDr. Jesús María Villar del Moral and Dr. José Luis Muñoz de Nova
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDr. José Luis Muñoz de Nova
    B.5.2Functional name of contact pointPrincipal Investigator
    B.5.3 Address:
    B.5.3.1Street AddressCalle Diego de león, 62
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28006
    B.5.3.4CountrySpain
    B.5.4Telephone number34915202372
    B.5.6E-mailjmunoz@salud.madrid.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Solución de Lugol Fuerte
    D.2.1.1.2Name of the Marketing Authorisation holderNot apply
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Oral solution
    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 INNSolución Fuerte de Lugol
    D.3.9.1CAS number 8500003-09-0
    D.3.9.2Current sponsor codeSolución Fuerte de Lugol
    D.3.9.3Other descriptive nameAQUEOUS IODINE SOLUTION
    D.3.9.4EV Substance CodeSUB12930MIG
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 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
    Graves-Basedow disease
    Enfermedad de Graves-Basedow
    E.1.1.1Medical condition in easily understood language
    Graves-Basedow disease
    Enfermedad de Graves-Basedow
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10065624
    E.1.2Term Graves-Basedow disease
    E.1.2System Organ Class 100000004860
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To analyze whether, in euthyroid patients undergoing TT due to GD, preoperative non-preparation with LS increases the appearance of postoperative complications compared to the use of LS preparation.
    Analizar si, en pacientes eutiroideos sometidos a tiroidectomía total por enfermedad de Graves, la no preparación preoperatoria con solución de Lugol incrementa la aparición de complicaciones postoperatorias frente a la utilización de dicha preparación.
    E.2.2Secondary objectives of the trial
    - To analyze whether, in patients undergoing TT, preoperative non-preparation with LS influences intraoperative results.
    - To analyze whether, in patients undergoing TT, preoperative non-preparation with LS influences the postoperative long of stay or the rate of readmissions, when compared with the group of patients who do receive such preparation.
    - To analyze if, in patients undergoing TT, preoperative non-preparation with LS does not increase the appearance of permanent complications, including hypoparathyroidism or RLN injury, when compared with the group of patients who do they receive this preparation.
    - Determine the safety profile of the use of the LS.
    - Detect if there are subgroups of patients undergoing TT, in which the non-preparation with LS is particularly beneficial or harmful.
    - Compare the results obtained according to the technical variations used by each unit.
    - Analizar si, en pacientes sometidos a TT, la no preparación preoperatoria con SL influye en los resultados intraoperatorios.
    - Analizar si, en pacientes sometidos a TT, la no preparación preoperatoria con SL influye en la estancia postoperatoria o la tasa de reingresos urgentes, cuando se comparan con el grupo de pacientes que sí reciben dicha preparación.
    - Analizar si, en pacientes sometidos a TT, la no preparación preoperatoria con SL no incrementa la aparición de complicaciones permanentes, incluyendo hipoparatiroidismo o lesión del nervio recurrente, cuando se comparan con el grupo de pacientes que sí reciben dicha preparación.
    - Determinar el perfil de seguridad del uso de la SL.
    - Detectar si existen subgrupos de pacientes sometidos a TT, en los que la no preparación con SL sea particularmente beneficiosa o perjudicial.
    - Comparar los resultados obtenidos en función de las variaciones técnicas empleadas por cada unidad.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - The age of the patient must be over 18 years of age.
    - The patient or his / her tutor, in cases where this is the case, has the capacity to understand the study and agrees to participate in it, by signing the corresponding informed consent document.
    - Patients who have been diagnosed with GD, defined as the existence of hyperthyroidism (TSH < lower limit of laboratory normality associated with TSI > upper limit of laboratory normality) that present ultrasonographic data (diffuse vascularization increase) and / or scintigraphy (diffuse uptake of the radioisotope) compatible with EG.
    - Euthyroid patients (free T4 and / or free T3 within the normal range of the laboratory) at the time of randomization, and under treatment with AT drugs (propylthiouracil, carbimazole or methimazole).
    - The patient must be proposed for total thyroidectomy, using a transcervical approach.
    - La edad del enfermo debe ser mayor de 18 años.
    - El paciente o su tutor, en los casos que así sea, tiene la capacidad para entender el estudio y acepta participar en el mismo, firmando el correspondiente documento de consentimiento informado.
    - Pacientes que hayan sido diagnosticados de EG, definida como la existencia de hipertiroidismo (TSH < límite inferior de la normalidad del laboratorio [LIN]) asociado a una elevación en los TSI (TSI > límite superior de la normalidad del laboratorio [LSN]) que presenten datos ecográficos (aumento difuso de la vascularización) y/o gammagráficos (captación difusa del radioisótopo) compatibles con EG.
    - Pacientes eutiroideos (T4 libre y/o T3 libre dentro del rango de normalidad del laboratorio) en el momento de la aleatorización, y bajo tratamiento con fármacos AT (propiltiouracilo, carbimazol o metimazol).
    - El paciente debe estar propuesto para tiroidectomía total, mediante abordaje transcervical.
    E.4Principal exclusion criteria
    - Prior cervicotomy by surgical intervention on the thyroid or parathyroid gland.
    - Associated hyperparathyroidism that requires associating a parathyroidectomy in the same surgical act.
    - Associated thyroid cancer that requires adding a lymph node dissection of the central or lateral compartment in the same surgical time.
    - Iodine allergy.
    - Consumption of lithium or amiodarone between randomization and administration of SL.
    - Patients with category IV of the anesthetic risk classification of the American Society of Anesthesiologists (ASA).
    - Women who breastfeed during the administration of the LS or in the month after it.
    - Preoperative palsy of a vocal cord verified by laryngoscopy.
    - Surgery performed by training specialists, or by staff not specifically dedicated to endocrine surgery.
    - Surgery not performed under general anesthesia.
    - Endoscopic surgery, video assisted or by remote approach.
    - Surgery performed in out-patient settings.
    - Current drug consumption or alcohol abuse that could interfere with meeting the study requirements.
    - Participation in any other trial with medications in the month prior to randomization.
    - Cervicotomía previa por intervención quirúrgica sobre la glándula tiroides o paratiroides.
    - Hiperparatiroidismo asociado que requiera asociar una paratiroidectomía en el mismo acto quirúrgico.
    - Cáncer de tiroides asociado que requiera añadir una disección ganglionar del compartimento central o lateral en el mismo acto quirúrgico.
    - Alergia al yodo.
    - Consumo entre la aleatorización y la administración de la SL de litio o amiodarona.
    - Pacientes con categoría IV de la clasificación de riesgo anestésico de la American Society of Anesthesiologists (ASA) (19).
    - Mujeres que den lactancia materna durante la administración de la SL o en el mes posterior a la misma.
    - Parálisis preoperatoria de una cuerda vocal constatada mediante laringoscopia.
    - Cirugía realizada por especialistas en formación, o por staff no dedicado específicamente a la cirugía endocrina.
    - Cirugía no realizada bajo anestesia general.
    - Cirugía endoscópica, videoasistida o mediante abordaje remoto.
    - Cirugía realizada en régimen de cirugía mayor ambulatoria.
    - Consumo actual de drogas o abuso de alcohol que pudiera interferir con el cumplimiento de los requisitos de estudio.
    - Participación en cualquier otro ensayo con medicamentos en el mes previo a la aleatorización.
    E.5 End points
    E.5.1Primary end point(s)
    The main variable will therefore be the appearance of at least one postoperative complication: hypoparathyroidism, RLN injury, postoperative hematoma, SSI or postoperative death.
    La variable principal será por tanto la aparición de al menos una complicación postoperatoria: hipoparatiroidismo, lesión del nervio recurrente, hematoma postoperatorio, infección de la herida quirúrgica o muerte postoperatoria.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    6 meses
    E.5.2Secondary end point(s)
    Preoperative variables
    - Demographic variables: birthdate, gender and ethnicity.
    - Drugs allergies. Allergy to iodine.
    - Personal history and usual treatment.
    - Aspects related to the GD: date of diagnosis, use of AT drugs and/or RI, existence of ophthalmopathy, existence of cervical compression symptoms and indication of surgery.
    - Physical exploration: body mass index, pulse at rest and blood pressure and cervical palpation.
    - Laboratory tests: hematocrit, leukocytes, neutrophils, platelets, INR, creatinine, potassium, total calcium, albumin, total proteins, PTH, 25-OH-vitamin D, free T4 and / or free T3, TSH, TSI.
    - Classification of the anesthetic risk of ASA.
    - Cervical ultrasound: existence of thyroid nodules and volume of the thyroid.
    - Mobility of the vocal cords evaluated by laryngoscopy.
    - Compliance with assigned treatment: the patient assigned to the LS arm must have consumed at least 80% of the total dose indicated.

    Intraoperative variables
    - Surgical time.
    - Antibiotic prophylaxis.
    - Intraoperative hemorrhage.
    - Thyroidectomy Difficulty Scale.
    - Loss of electromyographic signal during neural intraoperative monitorization.
    - Accidental parathyroidectomy.
    - Section or obvious lesion of the NLR.
    - Trachea or esophagus perforation.
    - Weight of the gland.
    - Electrosurgical hemostasis system used during the intervention.
    - Maneuvers used to check hemostasis.
    - Hemostats used during the intervention.
    - Use of drainage.
    - Definitive surgical technique: TT, unilateral or bilateral subtotal thyroidectomy or hemithyroidectomy.

    Postoperative variables
    - Early complications: hypoparathyroidism, RLN paralysis of the NLR, postoperative hematoma, SSI or death.
    - Debit for surgical drains.
    - Postoperative hospital long of stay.
    - Anatomopathological variables: histological diagnosis compatible with EG and existence of parathyroid glands in the surgical specimen.
    - Long-term complications: hypocalcemia and/or permanent vocal cord paralysis longer than 6 months
    Variables preoperatorias
    - Variables demográficas: fecha de nacimiento, género y etnia
    - Alergias medicamentosas. Alergia a yodo
    - Antecedentes personales y tratamiento habitual
    - Aspectos relacionados con la EG: fecha de diagnóstico, uso de fármacos AT, uso previo de RI, existencia de oftalmopatía, existencia de clínica compresiva cervical, indicación de la cirugía
    - Exploración física: índice de masa corporal, pulso en reposo y presión arterial, y palpación cervical
    - Pruebas de laboratorio: hematocrito, leucocitos, neutrófilos, plaquetas, INR, creatinina, potasio, calcio total, albúmina, proteínas totales, PTH, 25-OH-vitamina D, T4 libre y/o T3 libre, TSH, TSI
    - Clasificación del riesgo anestésico de la ASA
    - Ecografía cervical: se recogerá la existencia de nódulos tiroideos y volumen del tiroides
    - Movilidad de las cuerdas vocales evaluada mediante laringoscopia
    - Cumplimiento del tratamiento asignado: el paciente asignado al brazo de la SL deberá haber consumido al menos el 80% de la dosis total indicada

    Variables intraoperatorias
    - Tiempo quirúrgico
    - Profilaxis antibiótica
    - Hemorragia intraoperatoria
    - Thyroidectomy Difficulty Scale
    - Pérdida de señal electromiográfica detectada mediante NMI
    - Paratiroidectomía accidental
    - Sección o lesión evidente del NLR
    - Perforación de tráquea o esófago
    - Peso de la glándula
    - Sistema de hemostasia electroquirúrgica empleado durante la intervención
    - Maniobras empleadas para la comprobación de la hemostasia
    - Hemostáticos empleados durante la intervención
    - Uso de drenaje en el lecho quirúrgico
    - Técnica quirúrgica definitiva: TT, tiroidectomía subtotal uni o bilateral o hemitiroidectomía

    Variables postoperatorias
    - Complicaciones precoces: hipoparatiroidismo, parálisis del NLR, hematoma postoperatorio, infección del sitio quirúrgico o éxitus
    - Débito por los drenajes quirúrgicos
    - Estancia hospitalaria postoperatoria
    - Variables anatomopatológicas: diagnóstico histológico compatible con EG y existencia de glándulas paratiroides en la pieza quirúrgica.
    - Complicaciones a largo plazo: hipocalcemia y/o parálisis del NLR permanente
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 months
    6 meses
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    No tratamiento
    Non treatment
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    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 years
    E.8.9.1In the Member State concerned months21
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2019-04-30. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women Yes
    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 state270
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 270
    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 Decision2019-06-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-14
    P. End of Trial
    P.End of Trial StatusOngoing
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