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    Summary
    EudraCT Number:2013-000830-37
    Sponsor's Protocol Code Number:CP-4-005
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-07-12
    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 number2013-000830-37
    A.3Full title of the trial
    A Phase 3, Multicenter Study Designed to Evaluate the Efficacy and Safety of a Long Acting hGH Product (MOD-4023) in Adult Subjects with Growth Hormone Deficiency
    ESTUDIO MULTICÉNTRICO EN FASE 3 DISEÑADO PARA EVALUAR LA EFICACIA Y LA SEGURIDAD DE UN PRODUCTO DE HORMONA HUMANA DEL CRECIMIENTO (HGH) DE LIBERACIÓN PROLONGADA (MOD-4023) EN SUJETOS ADULTOS CON DEFICIENCIA DE LA HORMONA DEL CRECIMIENTO
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment with Long Acting hGH Product in Adult subjects with Growth Hormone Deficiency
    Tratamiento con el producto hGH de liberación prolongada en sujetos adultos con deficiencia de hormona de crecimiento
    A.4.1Sponsor's protocol code numberCP-4-005
    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 SponsorPROLOR Biotech Ltd.
    B.1.3.4CountryIsrael
    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 supportPROLOR Biotech Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPharmaNet/i3
    B.5.2Functional name of contact pointSenior Regulatory Affair Assiociate
    B.5.3 Address:
    B.5.3.1Street Address41 rue des Trois Fontanot
    B.5.3.2Town/ cityNanterre
    B.5.3.3Post code92000
    B.5.3.4CountryFrance
    B.5.4Telephone number+33975613243
    B.5.5Fax number+33975613243
    B.5.6E-mailRegOpsEurope@inventivhealth.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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/133/12
    D.3 Description of the IMP
    D.3.1Product namen/a
    D.3.2Product code MOD-4023
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNna
    D.3.9.1CAS number na
    D.3.9.2Current sponsor codeMOD-4023
    D.3.9.3Other descriptive nameRECOMBINANT HUMAN GROWTH HORMONE
    D.3.9.4EV Substance CodeSUB20678
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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 Yes
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/133/12
    D.3 Description of the IMP
    D.3.1Product namen/a
    D.3.2Product code MOD-4023
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNna
    D.3.9.1CAS number na
    D.3.9.2Current sponsor codeMOD-4023
    D.3.9.3Other descriptive nameRECOMBINANT HUMAN GROWTH HORMONE
    D.3.9.4EV Substance CodeSUB20678
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 Yes
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/133/12
    D.3 Description of the IMP
    D.3.1Product namen/a
    D.3.2Product code MOD-4023
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNna
    D.3.9.1CAS number na
    D.3.9.2Current sponsor codeMOD-4023
    D.3.9.3Other descriptive nameRECOMBINANT HUMAN GROWTH HORMONE
    D.3.9.4EV Substance CodeSUB20678
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 Yes
    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
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Adult or childhood onset growth hormone deficiency (GHD)
    Deficiencia de la hormona del crecimiento (DHC) manifestada en la niñez o en edad adulta.
    E.1.1.1Medical condition in easily understood language
    Adult or childhood onset growth hormone deficiency (GHD)
    Deficiencia de la hormona del crecimiento (DHC) manifestada en la niñez o en edad adulta.
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10056438
    E.1.2Term Growth hormone deficiency
    E.1.2System Organ Class 10014698 - Endocrine 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 demonstrate a clinical superiority of MOD-4023 over placebo in terms of decrease in Fat Mass (FM) in adult subjects with GHD
    Demostrar la superioridad clínica de MOD-4023 frente al placebo en lo que respecta a la disminución de la masa grasa (MG) en sujetos adultos con DHC
    E.2.2Secondary objectives of the trial
    ?To determine the efficacy of MOD-4023 over placebo in other body composition variables (such as lean body mass and waist-to-hip ratio)
    ?To evaluate the safety and tolerability of MOD-4023 over placebo in adult subjects with GHD
    ?To determine the IGF-I and IGFBP-3 serum levels
    ?Determinar la eficacia de MOD-4023 frente al placebo en lo que respecta a otras variables de la composición corporal como la masa corporal magra o el índice cintura-cadera
    ?Evaluar la seguridad y la tolerabilidad de MOD-4023 frente al placebo en sujetos adultos con DHC
    ?Determinar las concentraciones séricas del IGF-1 y la IGFBP-3
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women between the age of 23 to 70 years old at screening, inclusive
    2. GHD subjects as defined in the Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II (2007). The following cutoff values for the diagnosis of GHD will be used
    ? Insulin tolerance test or glucagon test, the validated cutoff for GHD in adults is a peak GH response ? 3 µg/L
    ? Growth-hormone-releasing hormone (GHRH) + arginine: for those with a body mass index:
    - BMI <25 kg/m2, a peak GH ?11 µg/L;
    - BMI 25?30 kg/m2 (included), a peak GH?8 µg/L;
    - BMI >30 kg/m2, a peak GH?4 µg/L.
    3. Subjects using hormonal replacement therapy(s) for deficiencies of other hypothalamo-pituitary axes must be on an optimized and stable treatment regimen (hormone levels within normal ranges on screening) for at least three months prior to screening:
    ? Temporary adjustment of glucocorticoid replacement therapy, as appropriate, is acceptable.
    ? Peripheral thyroid hormones (FT4) within the normal range of the central lab.
    ? Adrenal insufficiency ? subjects that are sufficient with documented test in last 6 months or on stable replacement.
    4. Subjects with Diabetes Insipidus should be on stable treatment for at least 6 months
    5. No rhGH replacement therapy or use of GH secretagogues for at least 9 months with any registered or investigational rhGH or GH secretagogue product.
    6. The IGF-I level at screening ?-1 SDS of the age and sex normal ranges according to the central laboratory measurements.
    7. For patients treated for Cushing's, at least two years elapsed since pituitary surgery and in biochemical remission without current medical therapy for the condition, documented within 6 months of study entry
    8. Body Mass Index (BMI, kg/m2) of 23.0 to 35.0 kg/m2, both inclusive
    9. Confirmed to be negative for anti r-hGH antibodies at the time of screening.
    10. Women of childbearing potential must agree to use appropriate contraceptive methods. For the purposes of this protocol, a history of tubal ligation, bilateral oophorectomy or hysterectomy, or post-menopausal women constitutes non-fertility. Fertile men must agree to use a barrier contraceptive (condom). Vasectomy older than 6 months is also acceptable.
    11. Women of childbearing potential must have a negative serum pregnancy test at inclusion.
    12. Up to date cancer screening according to ACS (American Cancer Society) Guidelines for the Early Detection of Cancer (breast, cervical, colon, skin and prostate).
    13. Subjects who are on a stable diet and exercise regime and do not have plans to modify their diet or exercise for at least 12 months.
    14. Subject had a DXA screening and the results are interpretable according to the study plan.
    15. Willing and able to provide written informed consent prior to performing any study procedures.
    1.Hombres y mujeres de entre 23 y 70 años en la selección, incluidos
    2.Los adultos con DHC de acuerdo con las Directrices de consenso para el diagnóstico y el tratamiento de adultos con deficiencia de la hormona del crecimiento de tipo II (2007). Se utilizarán los siguientes valores de corte para diagnosticar la DHC
    ?Prueba de tolerancia a la insulina o prueba del glucagón. El nivel de corte validado para la DHC en adultos es una respuesta máxima de HC ? 3 µg/l.
    ?Hormona liberadora de hormona del crecimiento (GHRH) + arginina: para quienes presenten un índice de masa corporal:
    - IMC <25 kg/m2, un pico de HC ? ?11 µg/l;
    - IMC 25?30 kg/m2 (incluidos), un pico de HC ? ?8 µg/l;
    - IMC >30 kg/m2, un pico de HC ? ?4 µg/l.
    3.Los sujetos que reciban tratamiento(s) de resustitución hormonal para deficiencias en otros ejes hipotalámico-pituitarios deberán estar recibiendo un régimen terapéutico optimizado y estable (concentraciones hormonales dentro de los intervalos normales en la selección) durante como mínimo los tres meses previos a la selección:
    ?El ajuste temporal y cuando corresponda de la terapia de resustitución de glucocorticoides se considera aceptable.
    ?Hormonas tiroideas periféricas (FT4) dentro del intervalo normal del laboratorio central.
    ?Insuficiencia suprarrenal: sujetos que alcancen una concentración suficiente en una prueba documentada durante los 6 últimos meses o con una terapia estable de resustitución.
    4.Los sujetos con diabetes insípida deben llevar un mínimo de 6 meses recibiendo un tratamiento estable.
    5.Ningún tratamiento de resustitución con r-hGH o administración de secretagogos de HC durante un mínimo de 9 meses con cualquier producto de r-hGH o secretagogo de HC registrado o en fase de investigación.
    6.Una concentración de IGF-1 en la selección ?-1 PDE (puntuaciones de desviación estándar) de los intervalos normales para la edad y el sexo según las evaluaciones del laboratorio central.
    7.En los pacientes con enfermedad de Cushing, deben haber transcurrido al menos dos años desde la intervención de la pituitaria y deben encontrarse en remisión bioquímica y no recibir tratamiento médico en la actualidad para la enfermedad, todo ello documentado en los 6 meses anteriores a la entrada en el estudio.
    8. Índice de masa corporal (IMC, kg/m2) de 23,0 a 35,0 kg/m2, ambos valores incluidos
    9.Confirmación de resultado negativo de anticuerpos contra r-hGH en el momento de la selección.
    10.Las mujeres potencialmente fértiles deben comprometerse a utilizar métodos anticonceptivos adecuados. Para los fines de este protocolo, una historia de ligadura de trompas, histerectomía u ovariectomía bilateral o las mujeres posmenopáusicas se consideran como infertilidad. Los hombres fértiles deben comprometerse a utilizar un método anticonceptivo de barrera (preservativo). También se considera aceptable una vasectomía realizada como mínimo 6 meses antes.
    11. Las mujeres potencialmente fértiles deberán obtener un resultado negativo en una prueba de embarazo en suero en el momento de la inclusión.
    12. Prueba de detección del cáncer de acuerdo con las directrices actualizadas de la ACS (Sociedad Estadounidense del Cáncer) para la detección precoz del cáncer (mama, cuello uterino, colon, piel y próstata).
    13. Sujetos que estén siguiendo una dieta y un régimen de actividad física estables y que no tengan previsto modificarlos durante un mínimo de 12 meses.
    14. Sujeto que tuviera una selección mediante DXA y cuyos resultados sean interpretables de conformidad con el plan del estudio.
    15. Sujetos dispuestos y capacitados para firmar un consentimiento informado por escrito antes de que se lleve a cabo cualquier procedimiento relacionado con el estudio.
    E.4Principal exclusion criteria
    1. Women who are pregnant or breast-feeding (at least 6 months delay from childbirth or lactation)
    2. Evidence of growth benign intracranial tumor within the last 12 months (determined by comparing a previous MRI to a new one obtained no more than 6 months prior to study entry to clarify dynamics of growth).
    3. History of any cancer. Exceptions to this exclusion criterion include resected in situ carcinoma of the cervix and squamous cell or basal cell carcinoma of the skin with complete local excision. Patients with GHD attributed to treatment of intracranial malignant lesions in childhood or adulthood (or, tumors) or leukemia may also be enrolled into the study provided that a recurrence-free survival period of at least 5 years is well documented in the study record.
    4. Signs of intracranial hypertension at screening
    5. Heart insufficiency, NYHA class > 2
    6. History of overt diabetes mellitus (including currently treated, well-controlled DM) defined according to the American Diabetes Association (ADA) Criteria. A history of gestational diabetes, resolved after childbirth, is not exclusionary.
    7. Impaired liver function defined as:
    a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than three times the upper limit of normal (ULN) at Screening visit in a patient without prior history of elevated LFTs 5(non-alcoholic fatty liver disease is not excluded, but requires etiological clarification prior to eligibility confirmation)
    OR
    b. Total bilirubin greater than 2 times the ULN at Screening
    8. Subjects with severe renal failure at the Screening visit (defined by GFR < 30 mL/min using MDRD Study Equation)
    9. History of Acromegaly
    10. For patients treated for Cushing's, biochemical, documented evidence of possible recurrence within 2 months of study entry according to 2008 Endocrine Society Guideline
    11. Active Carpal tunnel syndrome suspected on a recent history (last 6 months) or ongoing symptoms such as: Numbness, or tingling in hand and/or finger, pain in the arm, palm or forearm, both occurring also at night and with intensive use of the hand; trouble gripping objects and weakness in the thumb.
    12. Systemic corticosteroids other than in replacement doses within the 3 months before study entry (temporary adjustment of glucocorticoids, as appropriate, is acceptable)
    13. Anabolic therapy or supplements (subject to Medical Monitor's decision) other than gonadal steroid replacement therapy within 2 months before study entry
    14. History of non-compliance with medications, un-cooperativeness or drug abuse
    15. Subjects who, based on the investigator?s judgment, have a clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation. Conditions may include cardiovascular, peripheral vascular, pulmonary, hepatic, renal, or neurological disease, as determined by medical history, physical examination, laboratory tests or ECG.
    16. Subjects who participated in any study and had administration of an investigational medicinal product (IMP) within the last 2 months. Subjects with previous participation in investigational studies must have recovered from all adverse effects.
    17. Subjects who participated within the last 12 months in any clinical trial involving the use of medicinal products (investigational or approved) that impact insulin levels, or that included specific dietary or physical activity requirements are excluded
    18. History of positive serology to HBC, HBV and HIV (patients that have been previously vaccinated and therefore have positive serology are not excluded)
    19. Subjects with genetic causes of familial lipodystrophy.
    1. Mujeres embarazadas o en fase de lactancia (con un margen mínimo de seis meses entre el parto o la lactancia).
    2. Signos de crecimiento de tumor intracraneal benigno durante los 12 últimos meses (determinado comparando una RM previa con una nueva obtenida como máximo 6 meses antes de la inclusión en el estudio para establecer la dinámica del crecimiento).
    3. Antecedentes de cualquier tipo de cáncer. Las excepciones a este criterio de exclusión son: carcinoma localizado resecado del cuello uterino y carcinoma espinocelular o basocelular en la piel con escisión local completa. Pacientes con DHC atribuida al tratamiento de lesiones (o tumores) intracraneales malignas en la niñez o en edad adulta o de la leucemia también podrán ser incluidos en este estudio siempre y cuando se documente en la documentación del estudio una supervivencia sin recidiva de al menos 5 años.
    4. Signos de hipertensión intracraneal en la selección.
    5. Insuficiencia cardíaca, clase de la NYHA >2 (apéndice B).
    6. Historia de diabetes mellitus manifiesta (incluida la DM tratada en la actualidad y adecuadamente controlada) de acuerdo con los criterios de la ADA (Asociación Estadounidense de la Diabetes). La historia de diabetes gestacional, resuelta tras el parto, no es excluyente.
    7. Alteración de la función hepática, definida como:
    a. Alanina transaminasa (ALT) o aspartato transaminasa (AST) mayor que tres veces el límite superior de la normalidad (LSN) en la visita de selección en un paciente sin antecedentes previos de resultados elevados en las pruebas funcionales hepáticas (PFH; no se excluye la hepatopatía grasa no alcohólica, pero exige el aclaramiento etiológico antes de confirmar la elegibilidad).
    O BIEN
    b. Bilirrubina total mayor de 2 veces el LSN en la selección
    8. Sujetos con insuficiencia renal grave en la visita de selección (definida como GFR <30 ml/min de acuerdo con la ecuación del estudio MDRD)
    9. Historia de acromegalia
    10. En el caso de los pacientes tratados con enfermedad de Cushing, signos bioquímicos documentados de posible recidiva durante los 2 meses siguientes a la inclusión en el estudio de acuerdo con las directrices de 2008 de la Sociedad de Endocrinología
    11. Sospecha de síndrome del túnel carpiano activo o historia reciente (6 últimos meses) de síntomas en curso como: adormecimiento u hormigueo de las manos y/o los dedos, dolor en el brazo, la palma o el antebrazo, ambos también por la noche y tras un uso intensivo de las manos; problemas para agarrar objetos y debilidad del dedo gordo.
    12. Corticosteroides sistémicos al margen de dosis de resustitución durante los 3 meses anteriores a la entrada en el estudio (se considera aceptable, cuando corresponda, un ajuste temporal de los glucocorticoides).
    13. Tratamiento con anabolizantes o suplementos (sujeto a la decisión del monitor clínico) aparte de la terapia de resustitución con esteroides gonadales durante los 2 meses previos a la entrada en el estudio.
    14. Historia de incumplimiento del tratamiento, falta de colaboración o toxicomanía.
    15. Sujetos que, según el criterio del investigador, presenten una afección médica o quirúrgica significativa o inestable que pueda impedir una participación segura y completa en el estudio. Estas afecciones pueden incluir enfermedad cardiovascular, vascular periférica, pulmonar, hepática, renal o neurológica, determinada de acuerdo con la historia clínica, en la exploración física, con pruebas analíticas o con un ECG.
    16. Sujetos que hayan participado en cualquier estudio y a los que se haya administrado un medicamento en investigación (MEI) durante los 2 últimos meses. Los sujetos que hayan participado previamente en estudios de investigación deberán haberse recuperado de todos los efectos adversos.
    17. Se excluirá a los sujetos que hayan participado durante los 12 últimos meses en cualquier estudio clínico que implicase la administración de medicamentos (en investigación o aprobados) que afecten a las concentraciones de insulina o que incluyesen unos requisitos especiales en cuanto a la dieta o la actividad física.
    18. Historia de serología positiva de HBC, VHB y VIH (no se excluirá a los pacientes que se hayan vacunado previamente y que por lo tanto presenten una serología positiva).
    19. Sujetos con causas genéticas de lipodistrofia familiar.
    E.5 End points
    E.5.1Primary end point(s)
    Change in trunk FM, expressed in kilograms measured with DXA, from baseline to week 26
    Cambio en la MG troncal, expresada en kilogramos, medida mediante DXA, entre el inicio y la semana 26.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline and Week 26
    Baselnie y semana 26.
    E.5.2Secondary end point(s)
    Changes in body composition:
    ?Change in total FM, expressed in kilograms, measured with DXA, from baseline to 26 and 52 weeks
    ?Change in lean body mass, expressed in kilograms measured with DXA, from baseline to 26 and 52 weeks
    ?Change in trunk FM, expressed in kilograms measured with DXA, from baseline to 52 weeks
    ?Change in trunk FM, expressed as % change from baseline, measured with DXA, from baseline to 26 and 52 weeks
    Change in Biochemical markers:
    ?Change of IGF-I and IGF-I SDS levels across the visits
    ?Change of IGFBP-3 levels across the visits
    ?Proportion of subjects achieving normalization of IGF-1 levels during and at the end of the study

    Additional Measurements:
    ?Change in QoL
    ?Change in Waist-to-hip ratio
    ?Change in lipid profile: fasting HDL cholesterol, LDL cholesterol, triglycerides, Lp(a)

    Safety and Tolerability
    ?AEs and local tolerability (injection site reaction)
    ?Parameters of glucose metabolism:
    -Fasting insulin level
    -Fasting glucose levels
    -HbA1c levels
    ?Immunogenicity
    -Anti MOD-4023 Neutralizing Antibody occurrence
    ?IGF-I levels
    ?MOD-4023 levels
    ?Status of other hormonal axes
    -Thyroid hormones (Free T4, T3 and TSH)
    -Morning cortisol levels
    -Prolactin levels (screening, 6 months, 12 months)
    ?Other safety laboratory parameters, including serum chemistry profile, liver enzymes, hematology and urinalysis
    ?ECG (screening, 6 months, 12 months)
    ?Fundoscopy for the occurrence of increased intracranial pressure
    Cambios en la composición corporal:
    ?Cambio en la MG total, expresada en kilogramos, medida mediante DXA, entre el inicio y las semanas 26 y 52.
    ?Cambio en la masa magra corporal, expresada en kilogramos, medida mediante DXA, entre el inicio y las semanas 26 y 52.
    ?Cambio en la MG troncal, expresada en kilogramos, medida mediante DXA, entre el inicio y la semana 52.
    ?Cambio en la MG troncal, expresada como el cambio porcentual respecto al inicio, medida mediante DXA, entre el inicio y las semanas 26 y 52.

    Cambio en los marcadores bioquímicos:
    ?Cambio en las concentraciones de IGF-1 y de las PDE del IGF-1 en todas las visitas.
    ?Cambio en las concentraciones de IGFBP-3 en todas las visitas.
    ?Proporción de sujetos que logran la normalización de los niveles de IGF-1 durante y al final del estudio (semanas 26 y 52).

    Variables adicionales:
    ?Cambios en la CdV
    ?Cambio en el índice cintura-cadera
    ?Cambio en el perfil lipídico: colesterol HDL en ayunas, colesterol LDL, triglicéridos, Lp(a)

    Seguridad y tolerabilidad
    ?AA y tolerabilidad local (reacciones en el lugar de la inyección)
    ?Parámetros del metabolismo de la glucosa:
    -Concentración de insulina en ayunas
    -Glucemia en ayunas
    -Concentraciones de HbA1c
    ?Inmunogenia
    -Aparición de anticuerpos neutralizantes contra MOD-4023
    ?Concentraciones de IGF-1
    ?Concentraciones de MOD-4023
    ?Estado de otros ejes hormonales
    - Hormonas tiroideas (T4 libre, T3 y TSH)
    - Concentraciones matutinas de cortisol
    - Concentraciones de prolactina (selección, 6 meses, 12 meses)
    ?Otros parámetros analíticos de seguridad, incluido el perfil de química sérica, enzimas hepáticas, hematología y análisis de orina
    ?ECG (selección, 6 meses, 12 meses)
    ?Oftalmoscopia para evaluar el aumento de la presión intracraneal
    E.5.2.1Timepoint(s) of evaluation of this end point
    Changes in body composition from baseline to 26 and 52 weeks

    Change in Biochemical markers across the visits
    Additional Measurements

    Safety and Tolerability
    Cambios en la composición corporal entre el inicio y las semanas 26 y 52.

    Cambio en los marcadores bioquímicos en todas las visitas

    Variables adicionales:

    Seguridad y tolerabilidad
    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 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) 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA32
    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
    Austria
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Netherlands
    Poland
    Romania
    Russian Federation
    Serbia
    Slovakia
    Spain
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    última visita del último paciente incluido
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    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) No
    F.1.2.1Number of subjects for this age range: 170
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 75
    F.4.2.2In the whole clinical trial 189
    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)
    Standard care
    Tratamiento estándar de referencia
    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 Decision2013-10-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-26
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-06-11
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