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    Summary
    EudraCT Number:2016-003833-91
    Sponsor's Protocol Code Number:KF7013-02
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-08-10
    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 number2016-003833-91
    A.3Full title of the trial
    Randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of intravenous neridronic acid in subjects with complex regional pain syndrome (CRPS)
    Ensayo aleatorizado, doble ciego y controlado con placebo para investigar la eficacia y seguridad del ácido neridrónico intravenoso en sujetos con síndrome de dolor regional complejo (SDRC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of intravenous neridronic acid in CRPS
    Eficacia y seguridad del ácido neridrónico intravenoso en el SDRC
    A.4.1Sponsor's protocol code numberKF7013-02
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1187-8036
    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 SponsorGrünenthal GmbH
    B.1.3.4CountryGermany
    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 supportGrünenthal GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGrünenthal GmbH
    B.5.2Functional name of contact pointGrünenthal Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressZieglerstr. 6
    B.5.3.2Town/ cityAachen
    B.5.3.3Post code52078
    B.5.3.4CountryGermany
    B.5.4Telephone number492415693223
    B.5.6E-mailClinical-Trials@grunenthal.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 Yes
    D.2.1.1.1Trade name Nerixia 100 mg/8 mL concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderAbiogen Pharma S.p.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameNeridronic acid 100 mg/8 mL concentrate for solution for infusion
    D.3.2Product code GRT7013
    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 INNNERIDRONATE SODIUM
    D.3.9.1CAS number 80729-79-9
    D.3.9.2Current sponsor codeGRT7013
    D.3.9.3Other descriptive nameSodium neridronate hemihydrate
    D.3.9.4EV Substance CodeSUB27150
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for 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
    Complex Regional Pain Syndrome (CRPS).
    Síndrome de Dolor Regional Complejo (CRPS)
    E.1.1.1Medical condition in easily understood language
    Complex regional pain syndrome is a chronic, severely painful disabling condition. It can develop after a minor injury (fracture, sprain), usually in a distal extremity (hand, wrist, ankle, and foot).
    El CRPS es una afección incapacitante crónica y muy dolorosa. Puede desarrollarse tras una lesión menor (fractura, esguince), generalmente en una extremidad distal (mano, muñeca, tobillo y pie).
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10064334
    E.1.2Term Complex regional pain syndrome Type I
    E.1.2System Organ Class 100000004852
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10064335
    E.1.2Term Complex regional pain syndrome Type II
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the superior efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo for the treatment of CRPS-related pain.
    Demostrar la mayor eficacia de una dosis acumulada de 400 mg de ácido neridrónico intravenoso frente al placebo en el tratamiento del dolor asociado al SDRC.
    E.2.2Secondary objectives of the trial
    To assess the efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo for the treatment of CRPS-related pain.
    To assess the efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo on the dynamic mechanical allodynia (DMA).
    To assess the efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo on the pressure pain threshold (PPT).
    To assess the efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo on edema of the hand or foot.
    Evaluar la eficacia de una dosis acumulada de 400 mg de ácido neridrónico intravenoso frente al placebo en el tratamiento del dolor asociado al SDRC.
    Evaluar la eficacia de una dosis acumulada de 400 mg de ácido neridrónico intravenoso frente al placebo en la alodinia mecánica dinámica (AMD).
    Evaluar la eficacia de una dosis acumulada de 400 mg de ácido neridrónico intravenoso frente al placebo en el umbral de dolor a la presión (UDP).
    Evaluar la eficacia de una dosis acumulada de 400 mg de ácido neridrónico intravenoso frente al placebo en el edema de la mano o del pie.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Informed consent signed.
    2. Male or female subjects at least 18 years of age at Visit 1.
    3. A diagnosis of CRPS according to the clinical diagnostic criteria recommended by the International Association for the Study of Pain (IASP; “Budapest clinical criteria”), assessed at Visit 1. Signs and symptoms of CRPS must apply to an affected limb (arm or leg) and must demonstrate asymmetry with respect to the contralateral limb. The CRPS duration must be 2 years or less since onset of symptoms.
    4. A baseline average pain intensity score of greater than or equal to 4 using an 11-point NRS, referring to the CRPS-affected limb (average of pain recorded over 7 days). The baseline average pain intensity score will be calculated automatically by the electronic diary, which must be checked prior to allocation at Visit 2. A subject who has not met average baseline pain intensity requirements (at least 4 average pain intensity ratings) due to lack of compliance with the electronic diary may be rescheduled for Visit 2 (1 time only), with appropriate re-training to ensure compliance with use of the electronic diary.
    5. In stable treatment and follow-up therapy for CRPS for at least 1 month prior to allocation to treatment (Visit 2). Subjects must have failed attempts with at least 2 available treatments for CRPS, 1 of which must have been a pharmacologic treatment.
    6. Women of child-bearing potential must have a negative urine ß-HCG pregnancy test at Visit 1 and must be using 2 forms of medically acceptable contraception, including at least 1 highly effective method of contraception with a low failure rate, defined as less than 1% per year (e.g., oral contraceptives or intrauterine device), and a second medically acceptable method such as use of condoms with spermicide by their male partner. A barrier method alone is not acceptable. Highly effective methods of contraception must be used for at least 1 month prior to Visit 2 and for the duration of the trial. Male subjects must use condom and spermicide during intercourse and must take care that the female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as above, starting with Visit 2 until at least 4 weeks after the last IMP infusion.
    7. Subjects must be able to communicate meaningfully, be able to differentiate with regard to location and intensity of the pain, and be able to answer the questions in the questionnaires used in this trial (assistance in filling out the questionnaires may be provided, if required due to motor or other physical impairment).
    1. Haber firmado el consentimiento informado.
    2. Hombres o mujeres con una edad mínima de 18 años en la visita 1.
    3. Diagnóstico de SDRC conforme a los criterios de diagnóstico clínico recomendados por la International Association for the Study of Pain (IASP; «criterios clínicos de Budapest»), evaluados en la visita 1. Los signos y síntomas de SDRC deben estar presentes en una extremidad afectada (brazo o pierna) y deben mostrar una asimetría con respecto a la extremidad contralateral. La duración del SDRC debe ser de 2 años o menos desde el inicio de los síntomas.
    4. Puntuación basal media de la intensidad del dolor igual o superior a 4 mediante una NRS de 11 puntos, referida a la extremidad afectada por el SDRC (promedio del dolor registrado a lo largo de 7 días). La puntuación basal media de la intensidad del dolor será calculada automáticamente por el diario electrónico, que deberá comprobarse antes de la asignación en la visita 2. En el caso de que un sujeto no cumpla los requisitos de intensidad media del dolor basal (valor mínimo de 4 en la puntuación media de la intensidad del dolor) por incumplimiento del diario electrónico, podrá volver a ser programado para la visita 2 (solo 1 vez), tras insistir en las instrucciones con el fin de garantizar el cumplimiento del uso del diario electrónico.
    5. Haber recibido tratamiento estable y terapia de seguimiento para el SDRC durante al menos 1 mes antes de la asignación al tratamiento (visita 2). Fracaso previo de al menos 2 de los tratamientos disponibles para el SDRC, 1 de los cuales debe haber sido un tratamiento farmacológico.
    6. Las mujeres en edad fértil deberán obtener un resultado negativo en una prueba de embarazo mediante la determinación de ß-HCG en orina en la visita 1 y deberán utilizar 2 métodos anticonceptivos médicamente aceptables, al menos 1 de los cuales debe ser un método anticonceptivo muy eficaz con un bajo índice de fallos, inferior al 1% anual (p. ej., anticonceptivos orales o dispositivo intrauterino), y un segundo método médicamente aceptable, como el uso de preservativo con espermicida por parte de la pareja masculina. Un método de barrera solo no se considera aceptable. Estos métodos anticonceptivos muy eficaces deberán utilizarse durante al menos 1 mes antes de la visita 2 y durante todo el estudio. Los sujetos varones deberán utilizar preservativo con espermicida durante las relaciones sexuales y asegurarse de que su pareja femenina utilice al menos otro método anticonceptivo con un bajo índice de fallos, según lo definido anteriormente, a partir de la visita 2 y como mínimo hasta 4 semanas después de la última infusión del PI.
    7. Los sujetos deberán ser capaces de comunicarse de forma comprensible, de discriminar la localización y la intensidad del dolor y de contestar a las preguntas de los cuestionarios utilizados en este ensayo (se podrá proporcionar ayuda para cumpletar los cuestionarios en caso de que sea necesario debido a trastornos motores u otros impedimentos físicos).
    E.4Principal exclusion criteria
    1. Evidence of renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/min/1.73 m2 using the 2009 Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine equation [Levey et al. 2009] or a urinary albumin to creatinine ratio [ACR] greater than 150 mg/g), based on central safety laboratory data obtained prior to Visit 2.
    2. Serum calcium or magnesium outside of the central laboratory’s reference range, based on central safety laboratory data obtained prior to Visit 2; a history of hypocalcemia or a metabolic disorder anticipated to increase risk for hypocalcemia; anticipated need for any new drug with known potential to cause hypocalcemia during the trial.
    3. Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL (75 nmol/L), based on central safety laboratory data obtained prior to Visit 2. Subjects with vitamin D deficiency should receive appropriate supplementation during the Enrollment Period. A vitamin D level of at least 30 ng/mL (75 nmol/L) must be documented prior to allocation to IMP.
    4. Corrected QT interval (according to Fridericia’s formula; QTcF) greater than 470 ms (average of 3 ECGs obtained at Visit 1) according to central ECG reading facility evaluation or QTcF greater than 470 ms at pre-dose ECG at Visit 2 according to the investigator’s judgment; serum potassium outside the central laboratory’s reference range at Visit 1; clinically unstable cardiac disease.
    5. Subjects receiving medications with a known risk of torsades de pointes within 7 days prior to allocation. Subjects receiving selective serotonin re-uptake inhibitor antidepressants are eligible if the QT interval values do not meet the exclusion criteria, the medication was started at least 1 month prior to allocation, the dose is stable, and the dose is anticipated to remain stable throughout the trial.
    6. Any prior use of a bisphosphonate for treatment of CRPS, any prior administration of a bisphosphonate within the previous year, anticipated requirement for treatment with a bisphosphonate for another condition such as osteoporosis during the trial, or administration of denosumab (Prolia®) or other bone turnover suppressing drugs within 6 months prior to Visit 1.
    7. History of any allergic or hypersensitivity reaction to neridronic acid or other bisphosphonate, acetaminophen, or to vitamin D or calcium supplements.
    8. Recent tooth extraction or other invasive dental procedure (within 3 months prior to Visit 1), unhealed or infected extraction site, or significant dental/periodontal disease that may pre-dispose to need for tooth extraction or other invasive dental procedures during the trial. Subjects with indeterminate, suspicious or unreliable dental history, in the opinion of the investigator, must undergo a dental examination prior to receiving treatment.
    9. Evidence of denture-related gum trauma or improperly fitting dentures causing injury.
    10. Prior radiation therapy of the head or neck (within 1 year of Visit 1).
    11. History of malignancy within 2 years prior to Visit 1, with the exception of basal cell carcinoma.
    12. Nerve blocks, ketamine infusions, intravenous immunoglobulin, acupuncture, electromagnetic field treatment, or initiation/implementation of radiofrequency ablation or other sympathectomy procedures, or peripheral nerve stimulation within 6 weeks prior to Visit 1.
    13. Current alcohol or drug abuse, or history of alcohol or drug abuse within 2 years of Visit 1, based on subject history and physical examination and according to the investigator’s judgment.
    14. Any other severe medical condition, including severe depression, or any other severe mood disorder, that in the opinion of the investigator may affect efficacy or safety assessments or may compromise the subject’s safety during trial participation.
    15. Women who are pregnant or breastfeeding.
    16. Elevated AST or ALT greater than 2-fold upper limit of normal, based on central safety laboratory data obtained at Visit 1, or current evidence of chronic liver disease. Safety laboratory testing may be repeated prior to Visit 2, and subjects will be allowed in the trial if results of 2 consecutive tests, at least 3 days apart, are less than or equal to 2-fold upper limit of normal.
    17. Participation in another investigational drug trial within 3 months prior to Visit 1, or any previous trial involving neridronic acid, with the exception of subjects participating in KF7013-01 who were assigned to placebo and did not receive neridronic acid.
    18. Subject is engaged in litigation related to their disability from CRPS in which monetary gain or loss (or other compensation) may affect their objective participation in the trial.
    19. Subjects taking forbidden concomitant medications/therapies or not being able to follow the rules of use of concomitant treatment.
    20. Subjects incapable of giving informed consent.
    1.Indicios de insuficiencia renal (tasa de filtración glomerular estimada [TFGe] inferior a 30 ml/min/1,73 m2 calculada con la ecuación de la creatinina de la Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] de 2009 [Levey et al., 2009] o una proporción albúmina-creatinina [ACR] superior a 150 mg/g), según los datos de seguridad del laboratorio central obtenidos antes de la visita 2.
    2.Concentración sérica de calcio o magnesio situada fuera del intervalo de referencia del laboratorio central, según los datos de seguridad del laboratorio central obtenidos antes de la visita 2; antecedentes de hipocalcemia o de una alteración metabólica que previsiblemente pueda aumentar el riesgo de hipocalcemia (p. ej., hipoparatiroidismo); necesidad anticipada de cualquier fármaco nuevo que se sepa que puede provocar hipocalcemia durante el ensayo.
    3.Déficit de vitamina D, definido como un valor de 25(OH)D por debajo de 30 ng/ml (75 nmol/l), según los datos de seguridad del laboratorio central obtenidos antes de la visita 2. Los sujetos con déficit de vitamina D recibirán los suplementos necesarios durante el período de inclusión. Deberá documentarse un valor de vitamina D de al menos 30 ng/ml (75 nmol/l) antes de la asignación al PI.
    4.Intervalo QT corregido (según la fórmula de Fridericia; QTcF) superior a 470 ms (promedio de 3 ECG realizados en la visita 1) conforme a la evaluación realizada por el centro de interpretación central de ECG o QTcF superior a 470 ms en el ECG realizado en la visita 2 antes de la administración de la dosis, conforme al criterio del investigador; concentración sérica de potasio situada fuera del intervalo de referencia del laboratorio central en la visita 1; cardiopatía clínicamente inestable.
    5.Sujetos que hayan recibido medicamentos asociados a un riesgo conocido de torsades de pointes en los 7 días previos a la asignación. Los sujetos tratados con antidepresivos inhibidores selectivos de la recaptación de la serotonina elegibles si los valores del intervalo QT no cumplen los criterios de exclusión, si el tratamiento comenzó al menos 1 mes antes de la asignación, si la dosis es estable y si está previsto que se mantenga estable durante todo el ensayo.
    6.Cualquier uso previo de un bifosfonato para tratar el SDRC, cualquier administración previa de un bifosfonato en el año anterior, necesidad anticipada de administrar un bifosfonato para tratar otro trastorno, como la osteoporosis, durante el ensayo, o administración de denosumab (Prolia®) u otros fármacos inhibidores del remodelado óseo en los 6 meses anteriores a la visita 1.
    7.Cualquier antecedente de reacciones alérgicas o de hipersensibilidad al ácido neridrónico u otros bifosfonatos, al paracetamol o a los suplementos de vitamina D o calcio.
    8.Extracciones dentales u otros procedimientos dentales invasivos recientes (en los 3 meses anteriores a la visita 1), ausencia de cicatrización o infección de la zona de extracción, o enfermedad dental/periodontal importante (p. ej., molares incluidos, caries grave, focos de infección) que predispongan a la necesidad de realizar extracciones dentales u otros procedimientos dentales invasivos durante el ensayo. Los sujetos con unos antecedentes dentales indefinidos, sospechosos o poco fiables, en opinión del investigador, deberán someterse a una exploración dental antes de recibir el tratamiento.
    9.Evidencia de traumatismo gingival asociado a la dentadura postiza o de dentaduras postizas mal ajustadas que provocan lesiones.
    10.Antecedentes de radioterapia de cabeza o cuello (en el año anterior a la visita 1).
    11.Antecedentes de neoplasias malignas en los 2 años anteriores a la visita 1, salvo en caso de carcinoma basocelular.
    12.Uso de bloqueos nerviosos, infusiones de ketamina, inmunoglobulina intravenosa, acupuntura, tratamiento con campos electromagnéticos o inicio/aplicación de ablación por radiofrecuencia u otros procedimientos de simpatectomía, o estimulación de los nervios periféricos en las 6 semanas anteriores a la visita 1.
    13.Signos de abuso de alcohol o drogas en el momento actual o antecedentes de abuso de alcohol o drogas en los 2 años anteriores a la visita 1, en función de la anamnesis y la exploración física realizadas al sujeto y según el criterio del investigador.
    14.Cualquier otro problema médico grave, como depresión grave o cualquier otro trastorno grave del estado de ánimo, que en opinión del investigador pueda afectar a las evaluaciones de la eficacia y la seguridad o pueda comprometer la seguridad del sujeto durante su participación en el ensayo.
    15.Mujeres embarazadas o en período de lactancia.

    ** Por favor consultar el protocolo para conocer otros 4 criterios de exclusion. (Please consult the protocol to know other 4 exclusion criteria)
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline to Week 12 in the average pain intensity score (weekly average of pain values recorded daily in the electronic diary).
    Cambio desde el momento basal hasta la semana 12 en la puntuación media de la intensidad del dolor (promedio semanal de los valores diarios correspondientes al dolor registrados en el diario electrónico).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The change from the baseline phase (Day -7 to Day -1) to Week 12 will be analyzed.
    Se analizará el cambio entre la fase basal (del día -7 al día -1) y la semana 12.
    E.5.2Secondary end point(s)
    1. Change from baseline to Week 26 in the average pain intensity recorded on the tablet computer.
    2. Pain response to treatment, defined as at least 30% decrease from baseline in the average pain intensity at Week 12, recorded on the tablet computer.
    3. Pain response to treatment, defined as at least 30% decrease from baseline in the average pain intensity at Week 26, recorded on the tablet computer.
    4. Change from baseline to Week 12 in the pain intensity level of DMA.
    5. Change from baseline to Week 12 in the PPT ratio for the thenar muscle/abductor hallucis muscle.
    6. Change from baseline to Week 12 in the ratio of the figure of eight measurements of the affected limb versus the unaffected limb.
    1 Cambio desde el momento basal hasta la semana 26 en la intensidad media del dolor registrada en la tableta electrónica.
    2 Respuesta del dolor al tratamiento, definida como una disminución de al menos el 30% entre el momento basal y la semana 12 en la intensidad media del dolor registrada en la tableta electrónica.
    3 Respuesta del dolor al tratamiento, definida como una disminución de al menos el 30% entre el momento basal y la semana 26 en la intensidad media del dolor registrada en la tableta electrónica.
    4 Cambio desde el momento basal hasta la semana 12 en el grado de intensidad del dolor de la AMD.
    5 Cambio desde el momento basal hasta la semana 12 en el cociente del UDP en los músculos de la eminencia tenar/músculo abductor del dedo gordo.
    6 Cambio desde el momento basal hasta la semana 12 en el cociente entre las determinaciones del edema, por el método de la figura del ocho, en la extremidad afectada y la no afectada.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. The change from baseline (Visit 2 [Day 1]) to Visit 11 (Week 26) will be analyzed.
    2. The change from baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) will be analyzed.
    3. The change from baseline (Visit 2 [Day 1]) to Visit 11 (Week 26) will be analyzed.
    4. The change from baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) will be analyzed.
    5. The change from baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) will be analyzed.
    6. The change from baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) will be analyzed.
    1 Se analizará el cambio entre el momento basal (visita 2 [día 1]) y la visita 11 (semana 26).
    2 Se analizará el cambio entre el momento basal (visita 2 [día 1]) y la visita 8 (semana 12).
    3 Se analizará el cambio entre el momento basal (visita 2 [día 1]) y la visita 11 (semana 26).
    4 Se analizará el cambio entre el momento basal (visita 2 [día 1]) y la visita 8 (semana 12).
    5 Se analizará el cambio entre el momento basal (visita 2 [día 1]) y la visita 8 (semana 12).
    6 Se analizará el cambio entre el momento basal (visita 2 [día 1]) y la visita 8 (semana 12).
    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 No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    France
    Germany
    Korea, Republic of
    New Zealand
    Spain
    United States
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    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
    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: 324
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 56
    F.4.2.2In the whole clinical trial 360
    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 Decision2018-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-31
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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