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    Summary
    EudraCT Number:2014-003796-32
    Sponsor's Protocol Code Number:TV1106-IMM-30021
    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:2015-05-08
    Trial results View 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 number2014-003796-32
    A.3Full title of the trial
    A phase 3, multicenter, randomized, double-blind, placebo-controlled efficacy, safety and tolerability study of TV-1106 in growth hormone-deficient adults who are not current users of rhGH treatment
    Ensayo en fase III, multicéntrico, aleatorizado, doble ciego y controlado con placebo para evaluar la eficacia, la seguridad y la tolerabilidad de TV-1106 en adultos con déficit de hormona del crecimiento que no están actualmente en tratamiento con hormona de crecimiento recombinante humana (rhGH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study in adults with Growth Hormone Deficiency (GHD) who are not current users of growth hormone treatment to assess the efficacy, safety and tolerability of TV-1106 (experimental medicinal product)
    Ensayo clínico en adultos con déficit de hormona del crecimiento (GHD) que no están actualmente en tratamiento con hormona de crecimiento para evaluar la eficacia, la seguridad y la tolerabilidad de TV-1106 (producto en fase de investigación)
    A.4.1Sponsor's protocol code numberTV1106-IMM-30021
    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 SponsorTeva Pharmaceutical Industries 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 supportTeva Pharmaceutical Industries Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTeva Pharma GmbH
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressWaldecker Str. 7
    B.5.3.2Town/ cityMoerfelden-Walldorf
    B.5.3.3Post code64546
    B.5.3.4CountryGermany
    B.5.4Telephone number0034917088600
    B.5.6E-mailinfo-era-clinical@teva.de
    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 nameAlbutropin
    D.3.2Product code TV-1106
    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 INNNot available yet
    D.3.9.2Current sponsor codeTV-1106; Albutropin
    D.3.9.3Other descriptive nameRECOMBINANT HUMAN SERUM ALBUMIN (HSA) FUSED TO HUMAN GROWTH HORMONE (HGH)
    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 number50
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAlbutropin
    D.3.2Product code TV-1106
    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 INNNot available yet
    D.3.9.2Current sponsor codeTV-1106; Albutropin
    D.3.9.3Other descriptive nameRECOMBINANT HUMAN SERUM ALBUMIN (HSA) FUSED TO HUMAN GROWTH HORMONE (HGH)
    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 number100
    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
    Growth hormone deficiency
    Déficit de hormona del crecimiento
    E.1.1.1Medical condition in easily understood language
    Growth hormone deficiency (GHD) is a medical condition, caused by problems arising in the pituitary gland, in which the body does not produce enough growth hormone (GH).
    El déficit de hormona del crecimiento (GHD) es una dolencia causada por problemas que aparecen en la glándula pituitaria , en la que el cuerpo no produce suficiente hormona de crecimiento (GH).
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    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
    The primary objective of this study is to determine the efficacy of 6 months of treatment with TV-1106 compared with placebo on body fat composition.
    El objetivo principal del estudio es determinar la eficacia de 6 meses de tratamiento con TV-1106 en comparación con placebo en cuanto a la masa grasa corporal.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to assess additional body composition measures, insulin-like growth factor 1 standard deviation score (IGF-I SDS), quality of life (QOL), the safety, and tolerability of treatment, pharmacokinetics, pharmacokinetic/pharmacodynamic analysis, and pharmacogenomics (PGx) with TV-1106.
    Los objetivos secundarios del estudio abarcan la evaluación otras medidas de composición corporal tales como la puntuación de desviación estándar del factor de crecimiento insulinoide (PDE de IGF-I), la calidad de vida (CdV), la seguridad y la tolerabilidad del tratamiento, las características farmacocinéticas, la relación
    farmacocinética/farmacodinámica y la farmacogenómica (FG) de TV-1106.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacogenomics Substudy:
    Patients who have consented to participate in the voluntary PGx substudy will have blood samples collected at visit 2 (or subsequent visits). The samples will be stored for use in analysis of the assessment for possible associations between genetic polymorphisms and response to TV-1106 in terms of safety, pharmacokinetic and pharmacodynamic parameters. Evaluations will be based on results obtained from the patients as a phenotypic group.
    Subestudio farmacogenómico: Se recogerán las muestras de los pacientes que hayan otorgado su consentimiento para participar en el subestudio voluntario de FG durante la visita 2 (o en visitas posteriores). Dichas muestras se conservarán para los análisis de evaluación de posibles asociaciones entre polimorfismos genéticos y las respuestas a TV-1106 en términos de parámetros de seguridad, farmacocinéticos y farmacodinámicos. Las evaluaciones se
    basarán en los resultados obtenidos en pacientes de un mismo grupo fenotípico.
    E.3Principal inclusion criteria
    Patients may be included in the study if they meet all of the following
    criteria:
    a. provision of written informed consent and agreement to comply with study requirements
    b. males and females 18 years of age or over
    c. body mass index (BMI) between 19 and 35 kg/m2 inclusive
    d. diagnosis of adult GHD for at least 6 months, confirmed by medical record diagnostic testing specified by an accepted guidance (eg, Carroll 1998; Cook 2009; Ho 2007; Molitch 2011) in effect at the time of diagnosis or patients who have hypopituitarism from surgical resection
    e. no history of exposure to any rhGH within the past 12 months prior to screening
    f. IGF-I SDS level less than -1.0 at screening
    g. stable, adequate doses of replacement hormones (adrenal, thyroid, estrogen, testosterone, vasopressin) for at least 3 months prior to screening as clinically judged by the investigator to be adequate
    h. patients not receiving glucocorticoid replacement therapy must have adequate adrenal function confirmed by adrenocorticotropic hormone (ACTH) stimulation test at screening
    i. women of child-bearing potential must be willing to use a medically accepted method of contraception for the duration of the study and for 30 days after participation in the study (acceptable methods of contraception include: double barrier method [condom or diaphragm with spermicide], intrauterine device [IUD], partner?s vasectomy, or steroidal contraceptive [oral, transdermal, implanted, injected]). Patients who are gonadotropin deficient, surgically sterile, or at least 1 year post-menopausal are not required to use contraception.
    Únicamente se podrá incluir a los pacientes en el estudio si cumplen todos los criterios siguientes:
    a. otorgar su consentimiento informado por escrito y comprometerse a cumplir los requisitos del estudio;
    b. ser mujer u hombre y tener 18 años o más;
    c. IMC de entre 19 y 35 kg/m2, ambos extremos incluidos;
    d. diagnóstico de DGH del adulto documentado en la historia médica al menos 6 meses antes y confirmado mediante pruebas diagnósticas recogidas en la literatura de referencia vigente en el momento en el que se realice el diagnóstico (véase Carroll 1998; Cook 2009; Ho 2007; Molitch 2011) o pacientes con hipopituitarismo como resultado de
    una hipofisectomía;
    e. no haber estado expuestos a rhGH en los 12 meses anteriores a la selección;
    f. mostrar un valor de la PDE de IGF-I por debajo de ?1,0 en la selección;
    g. tratamiento de reposición hormonal con dosis adecuada y estable (p. ej.: suprarrenales, tiroideas, estrógenos, testosterona, vasopresina) durante al menos 3 meses antes de la selección y en función de lo que el investigador entienda como «adecuada» desde el
    punto de vista clínico;
    h. en pacientes sin tratamiento de reposición de glucocorticoides, deberá comprobarse que la función suprarrenal es adecuada mediante una prueba de estimulación con ACTH durante la selección;
    i. las mujeres fértiles deberán comprometerse a utilizar un método anticonceptivo aceptable desde el punto de vista médico durante el estudio y 30 días después de concluir su participación en el estudio (entre los métodos anticonceptivos aceptables encontramos:
    métodos de doble barrera [preservativo o diafragma con espermicida], DIU, pareja sometida a vasectomía o anticonceptivos hormonales [orales, transdérmicos, implantados o inyectados]; los pacientes con deficiencia de gonadotropina o esterilizados mediante
    una intervención quirúrgica o las mujeres postmenopáusicas durante al menos 1 año no están obligados a utilizar métodos anticonceptivos.
    E.4Principal exclusion criteria
    Patients will be excluded from participating in this study if they meet 1 or more of the following criteria:
    a. patients with acute or chronic conditions or diseases that could confound results of the study or put the patient at undue risk as determined by the investigator
    b. patients who have participated in another clinical trial with a new chemical/biological entity within 3 months of screening
    c. patients with known active malignancy (excluding surgically removed basal cell carcinoma or carcinoma in situ of cervix)
    d. patients with a previously treated pituitary tumor with evidence of tumor progression in the past year (evidence will be established by magnetic resonance imaging [MRI] or computerized tomography [CT] obtained within 3 months of screening or at screening. Patients will be excluded if they show any progression from a prior scan taken at least 12 months prior to the current scan.)
    e. patients with a new diagnosis of pituitary adenoma or other intracranial tumor within 12 months of screening
    f. presence of Prader-Willi syndrome, Turner?s syndrome, untreated adrenal insufficiency, active acromegaly in the past 5 years, or active Cushing?s syndrome in the past 1 year
    g. patients with known allergy or hypersensitivity to rhGH, HSA, yeast-derived products, or any other component of the formulation
    h. patients who are unable to undergo scanning by dual-energy x-ray absorptiometry (DXA) (eg, due to excessive body weight or implanted devices which would interfere with DXA)
    i. patients with previous signs or history of increased intracranial pressure (ICP) with rhGH treatment, or documented ICP or signs of ICP on fundoscopic examination at the time of screening (may be performed by investigator or referred to an ophthalmologist) Patients with previous history of ICP due to treated tumors that have resolved can be included in the study.
    j. patients with severe, clinically significant, persistent or recurring migraines, edema, or history or presence of carpal tunnel syndrome, or other nerve compression symptoms assessed as clinically important by the investigator
    k. patients with untreated or poorly controlled stage 2 hypertension (systolic blood pressure [SBP] ?150 mmHg and/or diastolic blood pressure [DBP] ?90 mmHg)
    l. patients with clinically significant abnormalities on the screening laboratory assessments, electrocardiogram (ECG), or physical examination that would confound the interpretation of the study or put the patient at undue risk of participation in the study as determined by the investigator.
    m. patients with type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus as indicated by a glycated hemoglobin (HBA1c) of ?8%
    n. patients who use anabolic steroids or corticosteroids except for physiological maintenance doses used as treatment for patients with hormone deficiencies. limited use of low dose glucocorticoid preparations is allowed (eg, topical preparations); inhaled budesonide will be permitted at a dose not to exceed 400 ?g/day for 3 days (total <1200 ?g/month) or equivalent.
    o. patients using weight reducing agents or appetite suppressants
    p. women who are pregnant or nursing, or planning pregnancy during the study period
    q. patients with active or known history of substance abuse that in the investigator?s opinion would affect compliance with the study
    r. patients with known tendency to have injection site lipoatrophy
    Los pacientes quedarán excluidos del estudio si presentan alguno de los criterios siguientes:
    a. pacientes con enfermedades agudas o crónicas que podrían alterar los resultados del estudio o poner al paciente en riesgo innecesariamente, según lo determine el investigador;
    b. pacientes que hayan participado en otro ensayo clínico con una nueva sustancia química o biológica en los 3 meses anteriores a la selección;
    c. pacientes con neoplasias malignas activas (salvo carcinoma basocelular o carcinoma de cuello uterino localizado extirpados mediante intervenciones quirúrgicas);
    d. pacientes con tumores hipofisarios cuya progresión durante el año previo esté documentada (dicha progresión deberá establecerse mediante una resonancia magnética (RM) o una tomografía axial computarizada (TAC) en los 3 meses previos a la selección o en el momento de selección); se excluirá asimismo a aquellos pacientes que muestren algún signo de progresión en pruebas de diagnóstico por la imagen tomadas al menos 12 meses antes de la prueba en el momento de selección);
    e. pacientes diagnosticados con adenoma hipofisario u otro tipo de tumor intracraneal en los 12 meses previos a la selección;
    f. presencia del síndrome de Prader-Willi, del síndrome de Turner, de insuficiencia suprarrenal sin tratamiento, de acromegalia activa en los últimos 5 años o de síndrome de Cushing en el último año;
    g. pacientes con antecedentes de alergia o hipersensibilidad a la rhGH, a la HSA, a productos derivados de levaduras o a cualquier otro componente de la formulación;
    h. pacientes que no puedan someterse a la DXA (ej.: por exceso de peso corporal o albergar implantes que interferirían con la prueba);
    i. pacientes con antecedentes o signos previos de HI al recibir tratamiento con rhGH, HI documentada o signos de HI en la oftalmoscopia realizada en el momento de selección (por el investigador o por un oftalmólogo). Los pacientes con antecedentes de HI por tumores tratados resueltos podrán ser incluidos en el estudio;
    j. pacientes con migrañas intensas, significativas desde el punto de vista clínico, persistentes o recurrentes, edema, presencia o antecedentes de síndrome del túnel carpiano u otro tipo de síntomas causados por la compresión de nervios que el investigador considere importantes desde el punto de vista clínico;
    k. pacientes con hipertensión de grado 2 (TAS >=150 mmHg y/o TAD >= 90 mmHg sin tratamiento o mal controlada);
    l. pacientes con anomalías clínicas significativas desde el punto de vista clínico en las pruebas de laboratorio, el electrocardiograma (ECG) o el reconocimiento físico realizados en el momento de la selección, que, a juicio del investigador, puedan alterar la interpretación de los resultados del estudio o poner al paciente en riesgo innecesariamente
    al participar en el estudio;
    m. pacientes con diabetes mellitus de tipo 1 o con diabetes mellitus de tipo 2 mal controlada, determinado por un valor de HBA1c >=8 %;
    n. uso de esteroides anabolizantes o corticoesteroides, salvo en el caso de dosis de mantenimiento utilizadas como tratamiento para pacientes con carencias hormonales (se permitirá un uso limitado de glucocorticoides a dosis bajas [ej.: medicamentos de uso tópico]; se permitirá el uso de inhaladores de budesonida, siempre que la dosis no supere los 400 ?g/día durante 3 días o una cantidad equivalente (en total, <1200 ?g/mes).
    o. uso de fármacos de adelgazamiento o anorexígenos;
    p. mujeres embarazadas, en periodo de lactancia o con intención de quedarse embarazadas durante el periodo del estudio;
    q. pacientes que sufran o tengan antecedentes de drogodependencia que, en opinión del investigador, pueda afectar al cumplimiento de las obligaciones derivadas del estudio;
    r. pacientes con tendencia a la lipoatrofia en el lugar de inyección.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy Variables and Endpoints:
    The primary endpoint is the change from baseline to week 24 in body fat mass (kg) as measured by DXA.
    Variables y criterios de valoración de la eficacia:
    El principal es la modificación entre el momento basal y la semana 24 de la masa corporal (kg) determinado mediante DXA.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    Semana 24
    E.5.2Secondary end point(s)
    Efficacy Variables and Endpoints:
    The secondary efficacy variables and endpoints for this study are as follows:
    - change from baseline to week 24 in total trunk fat (kg) as measured by DXA
    - change in IGF-I SDS from baseline to week 24
    - change in QOL scores from baseline to week 24 by questionnaire (assessment of GHD in adults [AGHDA])

    Other Efficacy Variables and Endpoints:
    - change from baseline to week 24 in lean body mass (DXA), percentage body fat (DXA), percentage trunk fat (DXA), and percentage change in trunk fat (DXA)
    - proportion of patients with IGF-I SDS within the normal range (-0.5 to +1.5) at week 24
    The following endpoints will be analyzed for all patients, and although all patients will receive TV-1106 during the 12-month extension phase, data will be analyzed by the original treatment assignment:
    - change from baseline to weeks 24, 48, and 72 in total trunk fat (DXA), lean body mass (DXA), percentage body fat (DXA), percentage trunk fat (DXA), and percentage change in trunk fat from week 24 through 72
    - change in IGF-I from baseline to week 24, week 48, and week 72 (IGF-I SDS)
    - change in lipids between baseline to week 24 and week 72 (as measured by total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, and lipoprotein)
    - change from baseline to week 48in QOL as measured by questionnaire (AGHDA) scores

    Exploratory Efficacy Variables and Endpoints:
    - change from baseline in QOL as measured by questionnaire (EQ5D-5L) scores and injection satisfaction questionnaire at all other time points

    Safety Variables and Endpoints:
    Safety variables and endpoints will include the following:
    - adverse event reports throughout the study
    - clinical laboratory test results
    - vital sign measurements
    - ECG findings and physical examination findings
    - concomitant medication usage throughout the study
    - changes in replacement hormones (thyroid stimulating hormone [TSH], free T4, total T3)
    - glucose homeostasis (HbA1c, fasting blood glucose, and insulin)

    Tolerability Variables and Endpoints:
    - proportion of patients who prematurely discontinue treatment
    - proportion of patients who prematurely discontinue treatment due to adverse events
    - time to premature treatment discontinuation
    - time to premature treatment discontinuation due to adverse events
    - proportion of patients with injection site reactions (patient questionnaire)
    - proportion of patients with lipoatrophy
    Las variables y criterios secundarios de valoración de este estudio son los siguientes:
    -Modificación entre el momento basal y la semana 24 del nivel de grasa troncal (en kg), determinada
    mediante DXA;
    -Modificación del valor de la PDE de IGF-I entre el momento basal y la semana 24.
    -Modificación de la puntuación de la CdV determinada mediante el cuestionario (evaluación con DGH
    en adultos [AGHDA]) entre el momento basal y la semana 24.
    Otras variables y criterios de valoración de la eficacia:
    -Modificación entre el momento basal y la semana 24 de la masa corporal magra, del porcentaje de
    grasa corporal, del porcentaje de grasa troncal y cambio porcentual del valor de grasa troncal (todos
    ellos determinados mediante DXA);
    -Proporción de pacientes cuyo valor de la PDE de IGF-I se sitúe en el intervalo normal (entre ?0,5 y
    +1,5) en la semana 24.
    Los siguientes criterios de valoración se analizarán en todos los pacientes y, a pesar de que todos ellos reciban TV-1106 durante la fase de extensión de 12 meses, los datos se analizarán en función del tratamiento original al que sean asignados:
    -Modificación entre el momento basal y las semanas 24, 48 y 72 del nivel de grasa troncal total, masa
    corporal magra, porcentaje de grasa corporal, porcentaje de grasa troncal (todos ellos determinados
    mediante DXA) y cambio porcentual del valor de grasa troncal entre la semanas 24 y 72;
    -Modificación del valor de IGF-I entre el momento basal y las semanas 24, 48 y 72 (en función del
    valor de la PDE de IGF-I);
    -Modificación de los lípidos entre el momento basal y las semanas 24 y 72 (determinaciones de colesterol total, colesterol de lipoproteína de baja densidad [LDL], colesterol de lipoproteína de alta densidad [HDL], triglicéridos y lipoproteínas);
    -Modificación entre el momento basal y la semana 48 de la CdV determinada por la puntuación
    obtenida en el cuestionario AGHDA.
    Otras variables y criterios de valoración de la eficacia:
    -Modificación desde el momento basal de la CdV determinada por las puntuaciones obtenidas en los
    cuestionarios EQ5D-5L y de satisfacción de la administración mediante inyección en el resto de puntos
    temporales.
    Variables y criterios de valoración de la seguridad:
    Las variables y criterios de valoración de la seguridad abarcarán los siguientes:
    -Notificación de acontecimientos adversos durante el estudio;
    -Resultados de las pruebas clínicas de laboratorio;
    -Mediciones de las constantes vitales;
    -Resultados de los ECG y de los reconocimientos físicos;
    -Uso de fármacos concomitantes a lo largo del estudio;
    -Modificaciones de los tratamientos de reposición hormonal (hormona estimulante de la tiroides [TSH],
    tiroxina libre [T4], triyodotironina total [T3]);
    -Homeostasis de la glucosa (HbA1c, glucosa en sangre en ayunas e insulina).
    Variables y criterios de valoración de la tolerabilidad:
    -Proporción de pacientes que suspenden anticipadamente el tratamiento;
    -Proporción de pacientes que suspenden anticipadamente el tratamiento por acontecimientos adversos;
    -Lapso de tiempo hasta la suspensión prematura del tratamiento;
    -Tiempo hasta la suspensión prematura del tratamiento por acontecimientos adversos;
    -Proporción de pacientes con reacciones en el lugar de inyección (cuestionario del paciente);
    -Proporción de pacientes que experimentan lipoatrofia.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 24, 48 and 72 or throughout the study - as specified above.
    Semana 24, 48 y 72 o a lo largo del estudio - tal como se especifica arriba
    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 No
    E.6.11Pharmacogenomic Yes
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Argentina
    Austria
    Belarus
    Brazil
    Bulgaria
    Canada
    Chile
    Croatia
    Czech Republic
    France
    Georgia
    Germany
    Greece
    Hungary
    Israel
    Italy
    Lithuania
    Mexico
    Peru
    Poland
    Romania
    Russian Federation
    Serbia
    Slovakia
    Slovenia
    Spain
    Sweden
    Turkey
    Ukraine
    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

    Patients who complete the study will be contacted via telephone call 2 weeks after the final dose of study drug (2 weeks after the end of the study) for safety follow up.
    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 months9
    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 months9
    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: 150
    F.1.3Elderly (>=65 years) No
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 150
    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)
    Normal treatment of the condition (Patients will be referred back to their physicians. Another commercially available growth hormone may be prescribed at the physician's recommendation).
    Tratamiento habitual de la dolencia (los pacientes serán referidos a sus médicos. Otra hormona de crecimiento disponible comercialmente puede ser recetada por recomendación del médico)
    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 Decision2015-07-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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