| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Schizophrenia |
| Esquizofrenia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Schizophrenia |
| Esquizofrenia |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039626 |
| E.1.2 | Term | Schizophrenia |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to test the hypothesis that mean weight gain, as assessed by change from baseline, will be statistically significantly less for flexibly dosed LY2140023 (20, 40, or 80 mg BID) than for flexibly dosed aripiprazole (10, 15, or 30 mg/day) in patients with
schizophrenia after 24 weeks of double-blind treatment. |
| El principal objetivo de este estudio es evaluar la hipótesis de que, en pacientes con esquizofrenia, el incremento promedio de peso tras 24 semanas de tratamiento doble ciego, será significativa y estadísticamente inferior cuando se administren dosis flexibles de LY2140023 (20, 40 u 80 mg BID) que cuando se administren dosis flexibles de aripiprazol (10, 15 ó 30 mg/día), de acuerdo con el cambio observado respecto al valor basal. |
|
| E.2.2 | Secondary objectives of the trial |
LY2140023 vs aripiprazole after 24 w double-blind treatment:
To test hypothesis proportion patients potentially clinically significant weight gain will be statistically significantly less for LY than aripiprazole
To evaluate safety and tolerability based on rates and time to discontinuation due to lack of tolerability defined as discontinuation due AE?s
To evaluate safety and tolerability respect changes from baseline in EPS.
To evaluate efficacy based on: Change from baseline in PANS; CGI-S; and NSA-16 scales; Incidence of response defined as a 30% decrease from baseline for PANSS
To evaluate efficacy w/in prospectively defined subpopulation measured by change from baseline on PANSS and other efficacy measures
To assess whether LY demonstrates improvement vs aripiprazole on health outcomes quality of life and functioning
To further evaluate efficacy safety and tolerability of LY through assessment of all efficacy and safety measures at end of 28-w open-label phase |
Evaluar hipótesis de incremento de peso estadística y significativamente inferior con LY2140023 tras 24 semanas.
Seguridad y tolerabilidad de LY2140023 y aripiprazol, según tasas de discontinuación y tiempo hasta discontinuación
Seguridad y tolerabilidad de LY2140023 y aripiprazol, respecto de basal de síntomas extrapiramidales; analíticas; constantes vitales; AAs; evaluación neurológica; y AA de tipo suicida
Eficacia de LY2140023 y aripiprazol en base a: - Cambio respecto de la basal de: PANSS y Subescalas; PSP; CGI-S; NSA-16.- Incidencia de respuestas (respuesta = 30% respecto a la puntuación total PANSS)
Eficacia de LY2140023 y aripiprazol en un subgrupo genético, desde basal a 24 semanas de la PANSS y otros criterios de eficacia.
Evaluar LY2140023 en comparación con aripiprazol, tras 24 semanas en relación con los resultados de salud, mediante: Cuestionario EQ-5D. - Cuestionario S-RUM - Escala SWN-S
Evaluar eficacia, seguridad y tolerabilidad de LY2140023, tras 28 semanas |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Patients are male or female, 18 to 65 years of age (inclusive) at study entry, with a diagnosis of schizophrenia as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR; APA 2000) (Disorganized, 295.10; Catatonic, 295.20; Paranoid 295.30; or Undifferentiated, 295.90) and confirmed by the Structured Clinical Interview for DSM-IV-TR (SCID).
[2] Female patients of childbearing potential must test negative for pregnancy at Visit 1 and agree to use a single, effective, medically acceptable method of
birth control, specifically: an oral contraceptive combined pill; an implantable contraceptive; an injectable contraceptive; a contraceptive patch (for women <198 pounds or 90 Kg); or an intrauterine device/system. The double-barrier method, as defined by two physical barriers such as a condom, diaphragm, or cervical occlusive cap, coupled with an additional barrier such as spermicidal foam, gel, film, cream or suppository, is also an acceptable method of birth control. Patients having undergone a hysterectomy or bilateral oophorectomy or other form of female sterilization, or patients having been medically confirmed to be post-menopausal, would not require any method of contraception. Menopausal women include women in either of the following categories:
[a] Spontaneous amenorrhea for at least 12 months, not induced by a
medical condition such as anorexia nervosa and not taking medications
during the amenorrhea that induced the amenorrhea (for example, oral
contraceptives, hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen receptor modulators (SERMs), or
chemotherapy). or [b] Spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH) level greater than 40mIU/mL.
[3] In the opinion of the investigator, at Visit 1, patients must require initiation of or modification to current antipsychotic treatment as outpatients.
[4] Patients must be considered reliable and have a level of understanding
sufficient to perform all tests and examinations required by the protocol, and be willing to perform all study procedures.
[5] Patients must be able to understand the nature of the study and have given their own informed consent. |
[1] Pacientes de ambos sexos, de edades comprendidas entre 18 y 65 años (ambos inclusive) en el momento de inclusión en el estudio, con diagnóstico de esquizofrenia, de acuerdo con la cuarta Edición del Manual diagnóstico y estadístico de los Trastornos Mentales, texto revisado (DSM-IV-TR; APA 2000) (Desorganizado, 295.10; Catatónico, 295.20; Paranoide 295.30; o indiferenciado, 295.90), confirmado mediante la Entrevista Clínica Estructurada para DSM-IV (SCID).
[2] Las mujeres en edad fértil deben presentar un resultado negativo en una prueba de embarazo que se realizará en la visita 1 y deberán estar de acuerdo en utilizar un único método anticonceptivo eficaz y aceptable, en concreto: una píldora anticonceptiva oral combinada; un anticonceptivo implantable; un anticonceptivo inyectable; un parche anticonceptivo (mujeres < 90 kg de peso); o un dispositivo / sistema intrauterino. También constituyen un método anticonceptivo aceptable los métodos de doble barrera, es decir, aquellos compuestos por dos barreras físicas, como preservativo, diafragma o capuchón cervical, junto con una barrera adicional (espermicidas: espuma, gel, película vaginal, crema o supositorio) No es necesario que sigan un método anticonceptivo las pacientes que se hayan sometido a una histerectomía u ooforectomía bilateral u otro método de esterilización, o aquellas pacientes posmenopáusicas cuya condición se haya confirmado médicamente. El término mujer posmenopáusica incluye las pacientes que:
[a] Hayan presentado amenorreas espontáneas durante al menos 12 meses, siempre que éstas no hayan sido producidas por enfermedades tales como anorexia nerviosa, y que no hayan tomado medicaciones durante dichas amenorreas que puedan haber inducido dicha amenorrea (por ejemplo, anticonceptivos orales, hormonas, hormona liberadora de gonadotropina, antiestrógenos, moduladores selectivos de los receptores de estrógenos (SERM) o quimioterapia).
o
[b] Hayan presentado amenorreas espontáneas durante 6-12 meses y una concentración de hormona estimulante del folículo (FSH) > 40 mUI/ml.
[3] De acuerdo con la opinión del investigador, en la visita 1 el paciente deberá requerir la administración de un tratamiento ambulatorio con antipsicóticos, o que se modifique el tratamiento antipsicótico que esté recibiendo.
[4] Debe considerarse que los pacientes son responsables y tienen un nivel de entendimiento suficiente para realizar todas las pruebas y evaluaciones especificadas en el protocolo, y que están dispuestos a realizar todos los procedimientos del estudio.
[5] Los pacientes deberán ser capaces de comprender la naturaleza del estudio, y haber proporcionado el consentimiento informado. |
|
| E.4 | Principal exclusion criteria |
[6] Are currently enrolled in, or discontinued within the last 60 days from, a clinical trial involving an investigational product or nonapproved use of a drug or device, or concurrently enrolled in any other type of medical research
[7] Are investigator site personnel directly affiliated with this study and/or their immediate families
[8] Lilly employees.
[9] on treatment with aripiprazole in the past 2 months or aripiprazole nonresponders.
[10] Patients for whom treatment with LY2140023 or aripiprazole is relatively or absolutely clinically contraindicated.
[11] Are hospitalized within 2 weeks of Visit 1 or have been hospitalized for anexacerbation of symptoms of schizophrenia with a discharge date in the past 2months
[12] Have any other current Axis I psychiatric diagnoses
[13] Have previously completed or withdrawn from this study, or any other study investigating LY2140023 or any predecessor molecules with glutamatergic activity
[14] Patients who have received an adequate treatment trial with clozapine at doses greater than 200 mg daily within 12 months prior to Visit 1, or who have received any clozapine at all during the month before Visit 1
[15] Patients who have a history of an inadequate clinical response to antipsychotic treatment for schizophrenia
[16] Patients who require concomitant treatment with any other medication with primary central nervous system activity
[17] Patients who have received treatment with any depot formulation of an antipsychotic medication within 1 dosing interval, minimum of 4 weeks prior to Visit 1.
[18] Patients have answered ?yes? to either Question 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the "Suicidal Ideation" portion of the C?SSRS, or answer "yes" to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the "Suicidal Behavior" portion of the C?SSRS; and the ideation or behavior occurred within the past month.
[19] diagnosis of substance dependence or abuse
[20] Diagnosis of substance-induced psychosis within 7 days of Visit 1 (or at any time during the study).
[21] Female patients who are pregnant, nursing, or who intend to become pregnant within 30 days of completing the study.
[22] Have known, uncorrected, narrow-angle glaucoma.
[23] Have a history of one or more seizures except for: A single simple febrile seizure between ages 6 months and 5 years or A single seizure with an identifiable etiology, which has been completely resolved.
[24] Patients who have had ECT within 3 months of Visit 1 or who will have ECT at any time during the study.
[25] Patients with untreated hyper- or hypothyroidism
[26] Have leukopenia or a history of leukopenia without a clear and resolved etiology, or known history of agranulocytosis during the patient?s lifetime.
[27] Patients with known medical history of Human Immunodeficiency Virus positive (HIV+) status.
[28] Test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody. Patients with positive Hepatitis B core antibody test and negative HBsAg may be included in the study if ALT/SGPT and AST/SGOT levels are less than 2 times the upper limit of normal (ULN) and total bilirubin does not exceed the ULN of the central laboratory
[29] Patients with ALT/SGPT or AST/SGOT values >2 times ULN of the performing laboratory, or total bilirubin values >1.5 times the ULN of the performing laboratory at Visit 1.
[30] Patients with acute, serious, or unstable medical conditions, including, but not limited to: inadequately controlled diabetes; severe hypertriglyceridemia; recent cerebrovascular accidents; acute systemic infection or immunologic disease; unstable cardiovascular disorders; malnutrition; or hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic or hematologic diseases
[31] Prolactin level at Visit 1 of >200 ng/mL with the exception of patients presently treated with risperidone. Patients treated with risperidone prior to study screening are excluded if their prolactin level is >300 ng/mL at Visit 1
[32] Patients with a corrected QT interval >450 msec (male) or >470 msec (female) at Visit 1
[33] Are incapable of participating in the study or are unwilling to engage in a meaningful way as study participants (for example, patients who are unresponsive or uncooperative with investigators or site personnel). This includes patients who, in the investigator?s opinion, demonstrate overtly aggressive behavior or who are deemed to pose a homicidal risk.
[34] Patients with moderate to severe renal impairment as defined by creatinine Clearance <60 ml/min at Visit 1. |
[6] Estar participando en la actualidad o haber abandonado en el transcurso de los 60 días previos un ensayo clínico.
[7] Ser personal del centro de investigación, directamente relacionado con el estudio, y/o familiares cercanos.
[8] Ser empleado de Lilly.
[9] Haber recibido tratamiento con aripiprazol en el transcurso de los 2 meses previos, o no haber respondido al tratamiento con aripiprazol.
[10] Pacientes en los que el tratamiento con LY2140023 o aripiprazol, está parcial o totalmente contraindicado.
[11] Haber sido hospitalizado en el transcurso de las 2 semanas previas a la visita 1, o haber sido hospitalizado debido a una exacerbación de los síntomas de esquizofrenia.
[12] Presentar otro trastorno psiquiátrico del eje I (DSM-IV-TR).
[13] Haber finalizado / abandonado este estudio u otro con LY2140023 u otra molécula con actividad glutamatérgica.
[14] Pacientes que, hayan recibido tratamiento con clozapina, o cualquier dosis de clozapina durante el mes previo a la visita 1.
[15] Pacientes que hayan presentado una respuesta clínica inadecuada al tratamiento con antipsicóticos para la esquizofrenia.
[16] Pacientes que requieran tratamiento concomitante con cualquier otra medicación con actividad sobre el sistema nervioso central (SNC),
[17] Pacientes que hayan recibido tratamiento con cualquier antipsicótico de liberación prolongada en el transcurso de 1 intervalo de administración (período mínimo de 4 semanas), previamente a la visita 1.
[18] Pacientes que hayan contestado afirmativamente bien a la pregunta 4 o a la 5, en la sección de "Ideación suicida" del cuestionario C-SSRS, o afirmativamente a cualquiera de los comportamientos suicidas, en la sección "Comportamiento suicida" del cuestionario C-SSRS, y dicha ideación o comportamiento se haya producido en el transcurso del último mes.
[19] Pacientes con diagnóstico de drogodependencia o drogadicción (según DSM-IV-TR), en los 6 meses previos a la visita 1.
[20] Pacientes con diagnóstico de psicosis inducida por drogas, en el transcurso de los 7 días previos a la visita 1.
[21] Pacientes que estén embarazadas, sean lactantes o deseen quedarse embarazadas en el transcurso de los 30 días posteriores a la finalización del estudio.
[22] Presentar glaucoma de ángulo estrecho no controlado.
[23] Presentar antecedentes de uno o más episodios convulsivos, excepto cualquiera de los 2 siguientes casos:
Un único episodio de convulsiones febriles simples, entre los 6 meses y los 5 años de edad
Un único episodio de convulsiones de etiología identificada, y que se haya resuelto completamente.
[24] Pacientes que hayan recibido TEC desde 3 meses antes a la visita 1, o que se sometan a dicho tratamiento en cualquier momento del estudio.
[25] Presentar hipertiroidismo o hipotiroidismo sin tratar.
[26] Presentar leucopenia (WBC < 3500/mm3, o 3,5 GI/l, o 3,5 103/ul) o antecedentes de leucopenia de etiología desconocida, o antecedentes de agranulocitosis (recuento absoluto de neutrófilos 500/mm3, o 0,5 GI/l, o 0,5 103/ul).
[27] Pacientes con VIH+.
[28] Presentar (1) anticuerpos frente a la hepatitis C ó (2) antígenos de superficie de la hepatitis B (HBsAg), con o sin anticuerpos frente al antígeno central de la hepatitis B.
[29] Presentar en la visita 1 una concentración de ALT/SGPT o AST/SGOT > 2 veces el límite superior de la normalidad (LSN), o una concentración de bilirrubina total > 1,5 veces el LSN del laboratorio que realice las pruebas analíticas.
[30] Presentar enfermedades agudas, graves o inestables, ver protocolo.
[31] Presentar en la visita 1 una concentración de prolactina > 200 ng/ml (> 200μg/l), excepto aquellos pacientes que estén siendo tratados con risperidona.
[32] Presentar en la visita 1 un valor del intervalo QT corregido de acuerdo con la fórmula de Bazett (QTcB) > 450 ms (varones) o > 470 ms (mujeres), basándose en la interpretación del ECG realizada en el proveedor central.
[33] Ser incapaz de participar en el estudio, o no estar dispuesto a colaborar durante su participación en el estudio.
[34] Presentar en la visita 1 una disfunción renal moderada/grave. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Weight will be measured at every visit to the nearest 0.1 kg. Patients should be weighed wearing light clothing, after evacuation of bladder contents and bowel contents when possible. Weight should be measured at a consistent time of day if possible, and on the same scale for every assessment. |
| En todas las visitas se determinará el peso del paciente, y éste se redondeará al 0,1 Kg más cercano. La medición se realizará con el paciente vestido con ropas ligeras y, si es posible, después de que éste haya evacuado vejiga e intestino. Si es posible, deberá pesarse al paciente a la misma hora del día, en la misma báscula |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks of double-blind treatment |
| 24 semanas tratamiento doble ciego |
|
| E.5.2 | Secondary end point(s) |
The following efficacy measures will be collected at the times shown in the Study Schedule:
Positive and Negative Syndrome Scale (PANSS)
Clinical Global Impression-Severity (CGI-S)
16-Item Negative Symptom Assessment (NSA-16) |
Las siguientes medidas de la eficacia se recogerán en los momentos indicados en el Calendario del Estudio:
Escala del Síndrome Positivo y Negativo (PANSS)
Escala de la Impresión Clínica Global de la gravedad (CGI-S)
Escala para la Evaluación de Síntomas Negativos de 16 ítems (NSA-16) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks of double-blind treatment |
| 24 semanas tratamiento doble ciego |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| France |
| Germany |
| Poland |
| Puerto Rico |
| Romania |
| Spain |
| Sweden |
| United States |
|
| E.8.7 | Trial 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
|
| ultima visita ultimo paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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