| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus |
| Diabetes Mellitus Tipo 2 |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049746 |
| E.1.2 | Term | Insulin-requiring type II diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition 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 demonstrate that LY2605541 is noninferior to insulin glargine for the change in HbA1c from baseline to 26 weeks of treatment in insulin naive patients with T2DM |
| El objetivo principal de este estudio consiste en demostrar que LY2605541 no es inferior a la insulina glargina en cuanto a la variación de la HbA1c entre el período basal y las 52 semanas de tratamiento en pacientes con DMT2 que no han recibido tratamiento previo con insulina utilizando un margen de no inferioridad (MNI) del 0,4%. |
|
| E.2.2 | Secondary objectives of the trial |
Gated:
1. Nocturnal hypoglycemia rate during the first 26 weeks of treatment
2. Proportion of patients with HbA1c <7.0% at 26 weeks and no nocturnal hypoglycemia during the first 26 weeks of treatment
3. HbA1c change from baseline after 26 weeks of treatment
4. Proportion of patients with HbA1c <7.0% after 26 weeks of treatment
5. Total hypoglycemia rate during the first 26 weeks of treatment
6. Fasting serum glucose (FSG) by laboratory measurement after 26 weeks of treatment
Non-Gated:
1. Total and nocturnal hypoglycemia rates
2. Total and nocturnal hypoglycemic incidences
3. Weight change from baseline
4. 6-point SMBG profile
5. Proportion of patients with HbA1c <7.0% at 52 and 78 weeks
6. Proportion of patients with HbA1c <7.0% and no nocturnal hypoglycemia at 52 and 78 weeks
7. Triglycerides), total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C)
8. Antibodies to LY2605541 |
Jerárquicos en relación a 52 sem de tratamiento: Tasa de hipoglucemia nocturna ;% de pacientes con una HbA1c < 7,0% y sin hipoglucemia nocturna ;Variación de la HbA1c; % de pacientes con una HbA1c < 7,0%; Tasa de hipoglucemia total ;Glucemia en ayunas.
Objetivos secundarios no jerárquicos en relación con los objetivos siguientes después de 26, 52 y 78 sem: Tasas de hipoglucemia total y nocturna; Incidencias de hipoglucemia total y nocturna; GA; Variabilidad intraindividual de la GA; Variación del peso; Perfil de ACG en 6 momentos del dia; % de pacientes con una HbA1c < 7,0% ; ? 6,5%; < 7,0% y sin hipoglucemia nocturna; Variación de la HbA1c con; HbA1c; Dosis de insulina; Ajustes de la dosis; TG, CE total, C-LDL y C-HDL; Anticuerpos contra LY2605541; Seguridad (AA, constantes vitales, exposición al tratamiento, otras medidas analíticas, etc.); Estado de salud ( [EQ-5D]) ; Satisfacción con el tratamiento ([ITSQ]); Encuesta sobre la hipoglucemia (LBSS). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] T2DM (per World Health Organization [WHO] Classification of Diabetes not treated with insulin
[2] Age 18 years of age or older
[3] Duration of diabetes ? 1 year
[4] Have been receiving at least 2 oral anti-hyperglycemic medications (OAMs) for at least 3 months prior to the study. Two or more medications may be contained in one pill. Doses of any OAMs are required to have been stable for the 3 months prior to screening and at least 2 of the OAMs must be dosed at or above half the maximum daily dose allowed by local regulations or the maximally tolerated dose of OAM.
? Note: OAMs must be used in accordance with the corresponding product label. Combination treatments of the OAMs are acceptable if they meet the above criteria. Combination medications should be counted as the number of individual components.
[5] HbA1c of 7.0% to 11.0%, inclusive, according to central lab at screening
[6] BMI ? 45 kg/m2
[7] Capable of, and willing to do the following:
? Inject insulin with a vial and syringe and perform self blood glucose monitoring, and
? Record keeping as required by this protocol, as determined by the investigator
[8] Have given written informed consent to participate in this study in accordance with local regulations
[9] Have access to a telephone
[10] Have refrigeration in the home
[11] This inclusion criterion applies to females of child-bearing potential (not surgically sterilized and between menarche and 1-year postmenopause) only.
? Are not breastfeeding.
? Test negative for pregnancy at the time of screening based on a urine pregnancy test.
? Intend not to become pregnant during the study.
? Have practiced a reliable method of birth control (for example, use of oral contraceptives or levonorgestrel; diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam; intrauterine devices; partner with vasectomy; or abstinence) for at least 6 weeks prior to screening.
? Agree to continue to use a reliable method of birth control during the study, as determined by the investigator (and for 2 weeks following the last dose of study drug). |
[1] Padecen DMT2 (según la Clasificación de la diabetes de la Organización Mundial de la Salud [OMS]) no tratada con insulina (Anexo 4).
[2] Tienen una edad mínima de 18 años.
[3] Han tenido diabetes durante al menos un año.
[4] Han estado recibiendo al menos 2 ADO durante 3 meses, como mínimo, antes del estudio. Un comprimido puede contener dos o más medicamentos. Las dosis de todos los ADO tendrán que haberse mantenido estables durante los 3 meses anteriores a la visita 1 y al menos 2 de los ADO tendrán que administrarse a una dosis equivalente o por encima de la mitad de la dosis diaria máxima permitida por la normativa local o a la dosis tolerada máxima del ADO.
? Nota: los ADO deben utilizarse de acuerdo con la ficha técnica correspondiente. Los tratamientos combinados de ADO son aceptables siempre que cumplan los criterios anteriores. Los medicamentos en combinación deben contabilizarse como el número de componentes individuales.
[5] Presentan una HbA1c de entre el 7,0% y 11,0%, ambos inclusive, con arreglo a la determinación del laboratorio central en la visita 1.
[6] Tienen un IMC ? 45 kg/m2.
[7] Presentan capacidad y disposición a hacer todo lo siguiente:
? Inyectarse la insulina con un vial y una jeringa y realizar ACG.
? Llevar los registros tal como exige este protocolo, según lo determinado por el investigador.
[8] Han otorgado su consentimiento informado por escrito para participar en este estudio de conformidad con la normativa local.
[9] Tienen acceso a un teléfono.
[10] Disponen de refrigeración en el domicilio.
[11] Este criterio de inclusión se aplica únicamente a las mujeres en edad fértil (no esterilizadas quirúrgicamente y entre la menarquia y un año después de la menopausia).
? No están en período de lactancia.
? Prueba de embarazo negativa en el momento de selección (visita 1) y aleatorización (visita 3) a tenor de una prueba de embarazo en suero.
? No tienen intención de quedarse embarazadas durante el estudio.
? Han empleado un método anticonceptivo fiable (por ejemplo, uso de anticonceptivos orales o levonorgestrel, diafragmas con gel espermicida, capuchón cervical con gel espermicida, preservativos con espuma espermicida, dispositivos intrauterinos, pareja con vasectomía o abstinencia) durante al menos 6 semanas antes de la selección.
? Se comprometen a seguir empleando un método anticonceptivo fiable durante el estudio, según lo determinado por el investigador (y durante dos semanas después de la última dosis del medicamento del estudio). |
|
| E.4 | Principal exclusion criteria |
[12] Have used insulin therapy anytime in the past 2 years, except for short-term treatment of acute conditions, and up to a maximum of 4 continuous weeks. Insulin use of any duration during pregnancy is not considered an exclusion criterion.
[13] Concomitant medications: rosiglitazone, pramlintide, glucagon-like peptide 1 (GLP-1) receptor agonist used concurrently or within 3 months prior to Visit 1.
[14] Local OAM restrictions: for patients on OAMs, restrictions for cardiac, renal, and hepatic diseases, local product regulations must apply.
[15] Weight loss medications: are currently taking, or have taken within the 3 months preceding Visit 1, prescription or over-the-counter medications to promote weight loss.
[16] Severe hypoglycemia history: have had any episodes of severe hypoglycemia within 6 months prior to Visit 1.
[17] Diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma: have had 1 or more episodes of ketoacidosis or hyperosmolar state/coma in the past 6 months.
[18] Have cardiac disease with functional status that is New York Heart Association Class III or IV
[19] Have a history of renal transplantation, or are currently receiving renal dialysis or have serum creatinine ?2 mg/dL (177 ?mol/L).
[20] Hepatic: have obvious clinical signs or symptoms of liver disease (excluding non-alcoholic fatty liver disease [NAFLD]), acute or chronic hepatitis, non alcoholic steatohepatitis (NASH), or elevated liver enzyme measurements as indicated below:
? total bilirubin ?2 x the upper limit of normal (ULN) as defined by the central laboratory, or
? alanine aminotransferase (ALT)/(serum glutamic pyruvic transaminase (SGPT) >2.5 x ULN as defined by the central laboratory, or
? aspartate aminotransferase (AST)/(serum glutamic oxaloacetic transaminase (SGOT) >2.5 x ULN as defined by the central laboratory.
[21] Have had a blood transfusion or severe blood loss within 3 months prior to Visit 1 or have known hemoglobinopathy, hemolytic anemia or sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with the measurement of HbA1c.
[22] Have active or untreated malignancy, have been in remission from clinically significant malignancy for less than 5 years, or at increased risk for developing cancer or a recurrence of cancer in the opinion of the investigator.
[23] Have known hypersensitivity or allergy to any of the study insulins or their excipients.
[24] Are receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy (excluding topical, intranasal, intraocular, and inhaled preparations) or have received such therapy within the 8 weeks immediately preceding Visit 1.
[25] Have fasting triglycerides >400 mg/dL (>4.5 mmol/L) at Visit 1 as determined by the central laboratory.
[26] Have irregular sleep/wake cycle in the investigator?s opinion.
[27] Have any other conditions that preclude the patient from following and completing the protocol.
[28] Lilly or Boehringer Ingelheim employees: are Lilly employees or Lilly representatives or Boehringer Ingelheim employees.
[29] Site personnel: are investigator site personnel directly affiliated with this study and/or their immediate families.
[30] Non-approved drug: have been treated with a drug within the last 30 days that has not received regulatory approval at the time of study entry.
[31] Prior study participation: are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or nonapproved use of a drug or device other than LY2605541, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
[32] Prior study with LY2605541: have previously completed or withdrawn from this study after having signed informed consent or any other study investigating LY2605541 after receiving at least 1 dose of investigational product.
[33] General restrictions: are unable and/or unwilling to provide informed consent, make themselves available for the duration of the study, or abide by study procedures and restrictions.
Additional exclusion criterion added for BIAJ Protocol Amendment(a):
[39] Lipid-lowering medications:
? are using niacin preparations as a lipid-lowering medication and bile acid sequestrants within 90 days prior to Visit 1; or,
? are using lipid-lowering medication at a dose that has not been stable for ?90 days prior to Visit 1.
If a patient has not been on a stable dose of lipid-lowering medication for ?90 days prior to Visit 1, the site should wait to screen the patient. If the results of the Visit 1 laboratory tests require a change to the patient's current lipid-lowering medication or initiation of lipid-lowering medication, it is acceptable to change the lipid-lowering medication for the patient and have the patient return ?90 days later to complete some of the Visit 1 procedures again. |
[12] Insulinoterapia (fuera del embarazo) en cualquier momento en los 2 años precedentes, salvo para el tratamiento a corto plazo de enfermedades agudas y durante un máximo de 4 semanas continuas.
[13] Medicamentos concomitantes: rosiglitazona, pramlintida o agonista del receptor del péptido glucagonoide 1 (GLP-1) utilizado de forma simultánea o en los 3 meses anteriores a la visita 1.
[14] Restricciones locales de ADO
[15] Medicamentos adelgazantes.
[16] Antecedentes de hipoglucemia intensa en los 6 meses anteriores a la visita 1.
[17] Cetoacidosis diabética (CAD) o coma hiperglucémico hiperosmolar no cetósico (CHHNC) en los 6 meses precedentes.
[18] Una cardiopatía con un estado funcional equivalente a la clase III o IV de la New York Heart
[19] Antecedentes de trasplante renal, están recibiendo diálisis renal en la actualidad o presentan una creatinina sérica ? 2 mg/dl (177 ?mol/l).
[20] Signos clínicos o síntomas evidentes de hepatopatía (salvo hepatopatía grasa no alcohólica [HGNA]), hepatitis aguda o crónica, esteatohepatitis no alcohólica (EHNA) o determinaciones elevadas de enzimas hepáticas tal como se indica a continuación:
? Bilirrubina total ? 2 veces el límite superior de la normalidad (LSN) definido por el laboratorio central.
? Alanina aminotransferasa (ALT)/(glutámico pirúvico transaminasa en suero (SGPT) > 2 veces el LSN definido por el laboratorio central.
? Aspartato aminotransferasa (AST)/(glutámico oxaloacético transaminasa en suero (SGOT) > 2 veces el LSN definido por el laboratorio central.
[21] Han recibido una transfusión de sangre o han tenido una hemorragia grave en los 3 meses anteriores a la visita 1 o presentan una hemoglobinopatía, anemia hemolítica, anemia drepanocítica o cualquier otro rasgo de anomalías en la hemoglobina que se sabe que interfiere en la determinación de la HbA1c.
[22] Tienen una neoplasia maligna activa o sin tratamiento, han estado en emisión de una neoplasia maligna con importancia clínica durante menos de 5 años o corren un riesgo elevado de presentar un cáncer o una recurrencia de un cáncer, en opinión del investigador.
[23] Hipersensibilidad o alergia conocida a alguna de las insulinas del estudio o de sus excipientes.
[24] Rstán recibiendo tratamiento crónico con glucocorticoides sistémicos (salvo preparados tópicos, intranasales, intraoculares e inhalados) o han recibido este tipo de tratamiento en las 8 semanas inmediatamente anteriores a la visita 1.
[25] Una concentración de triglicéridos en ayunas > 400 mg/dl (> 4,5 mmol/l) en la visita 1, según lo determinado por el laboratorio central.
[26] Ciclo de sueño/vigilia irregular en opinión del investigador.
[27] Presentan cualquier otro proceso (como drogadicción, alcoholismo o un trastorno psiquiátrico conocido) que descarta que el paciente siga y complete el protocolo.
[28] Empleados de Lilly o Boehringer Ingelheim: son empleados de Lilly o representantes de Lilly o empleados de Boehringer Ingelheim.
[29] Personal del centro: forman parte del personal del centro de investigación relacionado directamente con este estudio o sus familias inmediatas.
[30] Medicamentos no autorizados
[31] Participación previa en un estudio:
[32] Han finalizado previamente o se han retirado de este estudio después de haber firmado el consentimiento informado o cualquier otro estudio en que se investigue LY2605541 después de haber recibido al menos una dosis del producto en investigación.
[33] No son capaces o no se muestran dispuestos a otorgar su consentimiento informado
Criterio de exclusión adicional añadido en la enmienda (a) al protocolo BIAJ:
[39] Medicamentos hipolipemiantes
? uso de preparados de niacina como hipolipemiante y secuestradores de ácidos biliares en los 90 días anteriores a la visita 1, o
? uso de medicación hipolipemiante en una dosis que no se ha mantenido estable durante ? 90 días antes de la visita 1.
Cuando un paciente no haya recibido una dosis estable de medicación hipolipemiante durante ? 90 días antes de la visita 1, el centro tendrá que esperar para someter a selección al paciente. Si los resultados de las pruebas analíticas de la visita 1 exigen una modificación de la medicación hipolipemiante presente del paciente o el inicio de la administración de un hipolipemiante, resulta aceptable modificar la medicación hipolipemiante de ese paciente y hacer que acuda ? 90 días más tarde para realizar de nuevo algunos de los procedimientos de la visita 1 (véase el apartado 7.2.12). En el apartado 7.2.12 de este protocolo se facilita más información acerca de la medicación hipolipemiante en relación con este estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| A change of HbA1c from baseline to 52 weeks that is not inferior to glargine. |
| Cambio en HbA1C desde el inicio a 52 semanas que no es inferior a glargina |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 52 weeks of treatment |
| 52 semanas de tratamiento |
|
| E.5.2 | Secondary end point(s) |
| Nocturnal and total hypoglycemia rates and incidences superior to glargine, proportion of patients with HbA1c <7% at 26 weeks of treatment (also HbA1c <7% with no nocturnal hypoglycemia, FPG by laboratory, FBG by SMBG, weight change from baseline, SMBG 6-pt profile, HbA1c, insulin dose, number of dose adjustments to steady state, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, insulin and insulin analog antibodies, other safety endpoints such as serious adverse events, vitals, treatment-emergent adverse events, Health Outcomes measurements EQ-5D, ITSQ, and LBSS. |
| Tasas de hipoglucemia total y nocturna. Incidencias de hipoglucemia total y nocturna. GA . Variabilidad intraindividual de la GA .5 Variación del peso con respecto al período basal. 6 Perfil de ACG en 6 momentos del dia. 7 % de pacientes con HbA1c < 7,0%., HbA1c ? 6,5%, HbA1c < 7,0% y sin hipoglucemia nocturna. Cambio de la HbA1c con respecto al período basal . HbA1c. Dosis de insulina. Número de ajustes de la dosis hasta alcanzar el estado de equilibrio. Triglicéridos, colesterol total, C-LDL y C-HDL . Anticuerpos contra LY2605541. Otros criterios de valoración de la seguridad (acontecimientos adversos, constantes vitales, exposición al tratamiento, otras medidas analíticas, etc.). Cuestionario de salud: EuroQuol de 5 dimensiones [EQ-5D]), Cuestionario sobre la satisfacción con el tratamiento con insulina [ITSQ]).Encuesta sobre la hipoglucemia (LBSS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All gates objective endpoints are at 26 weeks of treatment for many of the non-gated secondary endpoints have various timepoints such as 0 to 12 weeks, 0 to 26 weeks, 0 to 52 weeks, 0 to 78 weeks, 12 to 26 weeks, 26 to 52 weeks, 52 to 78 weeks for nocturnal and total hypoglycemia incidences; 0 to 12 weeks, 0 to 52 weeks, 0 to 78 weeks, 12 to 26 weeks, 26 to 52 weeks, 52 to 78 weeks for nocturnal and total hypoglycemia rates; 52 and 78 weeks for FPG by laboratory, 52 and 78 weeks for proportion of patients with HbA1c <7%, and the same as immediately above with no nocturnal hypoglycemia, and HbA1c change from baseline |
| Los siguientes objetivos secundarios después del tratamiento al cabo de 26, 52 y 78 semanas |
|
| 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 | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 76 |
| 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 | No |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Czech Republic |
| Finland |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Lithuania |
| Mexico |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Turkey |
| United Kingdom |
| 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
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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