| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus with Moderate Renal Impairment (CKD 3A) |
| Diabetes mellitus tipo 2 e insuficiencia renal moderada (ERC 3A) |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045250 |
| E.1.2 | Term | Type II diabetes mellitus with renal manifestations |
| E.1.2 | System Organ Class | 100000004857 |
|
| 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 |
| To compare the mean change from baseline in HbA1c between dapagliflozin 10 mg and placebo, after 24 weeks of oral administration of double-blind treatment in patients with type 2 diabetes and CKD stage 3A. |
| Comparar la media del cambio respecto al momento basal en la HbA1c entre dapagliflozina 10 mg y placebo, después de 24 semanas de administración oral de tratamiento doble ciego en pacientes con diabetes tipo 2 y ERC en estadio 3A. |
|
| E.2.2 | Secondary objectives of the trial |
1, To compare the percent change from baseline in total body weight between dapagliflozin 10 mg and placebo, after 24 weeks of oral administration of double-blind treatment.
2, To compare the change from baseline in fasting plasma glucose (FPG) between dapagliflozin 10 mg and placebo, after 24 weeks of oral administration of double-blind treatment.
3, To compare the change from baseline in seated systolic blood pressure (SBP) between dapagliflozin 10 mg and placebo, after 24 weeks of oral administration of double-blind treatment. |
1. Comparar el cambio porcentual respecto al momento basal en el peso corporal total entre dapagliflozina 10 mg y placebo, después de 24 semanas de administración oral de tratamiento doble ciego.
2. Comparar el cambio respecto al momento basal en la glucosa plasmática en ayunas (GPA) entre dapagliflozina 10 mg y placebo, después de 24 semanas de administración oral de tratamiento doble ciego.
3. Comparar el cambio respecto al momento basal en la presión arterial sistólica (PAS) en sedestación entre dapagliflozina 10 mg y placebo, después de 24 semanas de administración oral de tratamiento doble ciego. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1, Female or male aged > or = 18 years and <75 years.
2, History of T2DM for more than 12 months.
3, Inadequate glycemic control, defined as HbA1c > or = 7.0% and < or = 11% measured at Screening. Note that HbA1c will be rechecked at Visit 4, and must then be > or = 7.0 and < or =10.5% (value from blood sample obtained at Visit 3) for patient to be randomized.
4, Stable anti-diabetic treatment regimen, defined as stable diet and exercise therapy alone or in combination with any or both of the two following alternatives:
-A regimen of any approved oral anti-diabetic medication (except SGLT2-inhibitors) where no dose-changes have occurred during 12 weeks before randomization
-Long acting or intermediate acting insulin and mixed insulin permitted as long as the dose is stable during last 12 weeks before randomization, changes ± 10% are allowed (in relation to number of units at randomization).
5, Renal impairment: CKD 3A
-eGFR* 40 - 65 mL/minute/1.73 m2 at Visit 2 (value from blood sample obtained at Visit 1) to enter the lead-in period.
-eGFR* 45 - 59 mL/minute/1.73 m2 at Visit 4 (average value calculated from the eGFR values at Visit 2 and Visit 3) for randomization.
*according to the re-expressed abbreviated (four-variable) MDRD Study equation, using central laboratory measurements of serum creatinine(sCr). [eGFR (mL/min/1.73m2) = 175 x (standardized sCr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if Black)] [Note: sCr reported in mg/dL] |
1.Mujer o varón de > o = 18 años y <75 años
2.Antecedentes de DMT2 durante más de 12 meses.
3.Control glucémico inadecuado, definido como HbA1c > o = 7,0% y < o = 11% medida en la inclusión. Obsérvese que la HbA1c se volverá a comprobar en la visita 4 y debe ser > o = 7,0 y < o = 10,5% (valor de la muestra de sangre obtenida en la visita 3) para aleatorizar al paciente.
4.Régimen de tratamiento antidiabético estable, definido como terapia con dieta estable y ejercicio sola o en combinación con cualquiera de las dos siguientes alternativas o con ambas:
-Un régimen de cualquier medicación antidiabética oral aprobada (salvo inhibidores de SGLT2) y en el que no se hayan producido cambios en la dosis durante las 12 semanas anteriores a la aleatorización.
-Se permite el uso de insulina de acción larga o intermedia e insulina mixta siempre que la dosis sea estable durante las 12 últimas semanas antes de la aleatorización, se permiten cambios de ± 10% (en relación con el número de unidades en la aleatorización).
5. Insuficiencia renal: ERC 3A
- TFGe* 40 - 65 ml/minuto/1,73 m2 en la visita 2 (valor de la muestra de sangre obtenida en la visita 1) para entrar en el período de preinclusión.
- TFGe* 45 - 59 ml/minuto/1,73 m2 en la visita 4 (valor promedio calculado a partir de los valores de la TFGe en la visita 2 y la visita 3) para la aleatorización.
*de acuerdo con la ecuación del ensayo MDRD reformulada abreviada (cuatro variables), usando las mediciones del laboratorio central de creatinina sérica (SCr). [TFGe (ml/min/1,73m2) = 175 x (SCr normalizada)-1.154 x (Edad)-0.203 x (0,742 si es mujer) x (1,212 si es de raza negra)] [Nota: SCr expresada en mg/dl] |
|
| E.4 | Principal exclusion criteria |
1, Women of childbearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period.
2, Women who are pregnant or breastfeeding.
3, Aspartate Aminotransferase (AST) >3X ULN.
4, Alanine Aminotransferase (ALT) >3X ULN.
5, Total Bilirubin (TB) >2 mg/dL (35 ?mol/L).
6, Serum Potassium (K) >5.5 meq/L (5.5 mmol/L).
7, Serum Calcium (Ca) <8 mg/dL or > ULN (<1.99 mmol/L or > ULN).
8, Positive for hepatitis B surface antigen.
9, Positive for anti-hepatitis C virus antibody.
10, Hemoglobin < or = 9.0 g/dL (90 g/L).
11, History of diabetes insipidus.
12, Symptoms of poorly controlled diabetes that would preclude participation in this study including but not limited to marked polyuria and polydipsia with greater than 10% weight loss during the three months prior to signing the consent at visit 1, or other signs and symptoms.
13, History of diabetic ketoacidosis or hyperosmolar nonketotic coma.
14, History of > or = 2 major hypoglycemic events in the 3 months prior to enrolment, defined as symptomatic events requiring external assistance due to severe impairment in consciousness or behaviour, with blood glucose level <3.0 mmol/L, <54 mg/dL (plasma glucose level <3.5 mmol/L, <63 mg/dL) and prompt recovery after glucose or glucagon administration.
15, Severe uncontrolled hypertension defined as SBP > or = 180 mmHg and/or DBP > or = 110 mmHg at any visit up to randomization.
17, Any of the following CV/Vascular Diseases within 3 months of prior to signing the consent at visit 1:Myocardial infarction, Cardiac surgery or revascularization (CABG/PTCA), Unstable angina, Unstable heart failure (HF), HF New York Heart Association (NYHA) Class IV,Transient ischemic attack (TIA) or significant cerebrovascular disease, Unstable or previously undiagnosed arrhythmia.
18, History of any biopsy or imaging verifying intercurrent kidney disease (such as glomerular nephritis or sign of renal artery stenosis) other than diabetic nephropathy or diabetic nephropathy with nephrosclerosis.
19, History of renal transplant.
20, Hemodialysis, ultrafiltration therapy, or peritoneal dialysis within 6 months prior to signing the consent at visit 1.
21, Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic insufficiency.
22, Documented history of hepatotoxicity with any medication.
23, Documented history of severe hepatobiliary disease.
24, Malignancy within 5 years of the enrolment visit (with the exception of treated basal cell or treated squamous cell carcinoma).
25, Known immunocompromised status, including but not limited to, individuals who have undergone organ transplantation or who are positive for the human immunodeficiency virus (HIV).
26, History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 2.
27, Long term treatment with glucocorticoids (two temporary periods of no longer than 10 days each are allowed during the study); topical or inhaled corticosteroids are allowed.
28, A metformin dose which is outside the specified dose range for moderate renal impairment (eGFR 30-59 mL/minute/1.73m2, MDRD formula) according to local guidelines and investigator´s judgement.
29, Ongoing treatment with any SGLT2-inhibitor at screening.
30, History of bariatric surgery or lap-band procedure.
31, Administration of sibutramine, phentermine, orlistat, rimonabant, benzphetamine, diethylpropion, methamphetamine, Victoza (liraglutide) indicated for anti-obesity treatment, and/or phendimetrazine, within 30 days prior to signing the consent at visit 1.
32, Patient who, in the judgment of the Investigator, may be at risk for dehydration or volume depletion due to co-existing conditions.
33, Patient with any condition which, in the judgment of the Investigator, may render the patient unable to complete the study or which may pose a significant risk to the patient.
34, Patient is currently abusing alcohol or other drugs or has done so within the last 6 months prior to signing the consent at visit 1.
35, Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
36, Previous enrolment in the present study.
37, Participation in another clinical study with an IP during the last 30 days prior to signing the consent at visit 1. |
1.Las mujeres fértiles (MF) que no acepten o no puedan usar un método anticonceptivo aceptable durante el período de ensayo completo.
2.Mujeres que estén embarazadas o en periodo de lactancia.
3.Aspartato aminotransferasa (AST) >3X LSN.
4.Alanina aminotransferasa (ALT) >3X LSN.
5.Bilirrubina total (BT) >2 mg/dl (35 ?mol/l).
6.Potasio (K) sérico >5,5 meq/l (5,5 mmol/l).
7.Calcio (Ca) sérico <8 mg/dl o >LSN (<1,99 mmol/l o >LSN).
8.Positivo para el antígeno de superficie del virus de la hepatitis B.
9Positivo para el anticuerpo contra el virus de la hepatitis C.
10.Hemoglobina < o = 9,0 g/dl (90 g/l).
11.Antecedentes de diabetes insípida.
12.Síntomas de diabetes mal controlada que imposibilite la participación en este ensayo, incluyendo, entre otros, poliuria y polidipsia marcadas con más de un 10% de pérdida de peso durante los tres meses anteriores a la firma del consentimiento en la visita 1 u otros signos y síntomas.
13.Antecedentes de cetoacidosis diabética o coma hiperosmolar no cetónico.
14.Antecedentes de > o = 2 acontecimientos hipoglucémicos mayores en los 3 meses previos al reclutamiento, definido como acontecimientos sintomáticos que requieren ayuda externa debido a una pérdida de consciencia grave o a una grave alteración del comportamiento, con niveles de glucosa en sangre <3,0 mmol/l, <54 mg/dl (nivel de glucosa plasmática <3,5 mmol/l, <63 mg/dl) y una recuperación rápida después de la administración de glucosa o glucagón.
15.Hipertensión grave no controlada definida como PAS > o = 180 mmHg y/o PAD > o = 110 mmHg en cualquier visita hasta la aleatorización.
16.Cualquiera de las siguientes enfermedades CV/vasculares en los 3 meses anteriores a la firma del consentimiento en la visita 1: Infarto de miocardio, cirugía cardíaca o revascularización (IDAC/ACTP), angina inestable, insuficiencia cardíaca (IC) inestable, IC de clase IV de la New York Heart Association (NYHA), accidente isquémico transitorio (AIT) o enfermedad cerebrovascular importante, arritmia inestable o sin diagnosticar previamente.
17.Antecedentes de cualquier biopsia o estudio de imagen que verifique enfermedad renal intercurrente (tal como nefritis glomerular o signo de estenosis arterial renal) diferente de nefropatía diabética o nefropatía diabética con nefroesclerosis.
18.Antecedentes de trasplante renal.
19. Hemodiálisis, terapia de ultrafiltración o diálisis peritoneal en los 6 meses anteriores a la firma del consentimiento en la visita 1.
20. Enfermedad hepática significativa, incluyendo, entre otras, hepatitis activa crónica y/o insuficiencia hepática grave.
21.Antecedentes documentados de hepatotoxicidad con cualquier medicación.
22.Antecedentes documentados de enfermedad hepatobiliar grave.
23. Neoplasia maligna en los 5 años anteriores a la visita de reclutamiento (salvo en el caso de carcinoma basocelular o carcinoma espinocelular tratado).
24. Estado inmunodeprimido conocido, incluyendo, entre otros, individuos que se han sometido a trasplante de órganos o con serología positiva para el virus de la inmunodeficiencia humana (VIH).
25.Antecedentes de hematuria microscópica o macroscópica inexplicada o hematuria microscópica en la visita 2.
26. Tratamiento a largo plazo con glucocorticoides (se permiten dos períodos temporales de no más de 10 días cada uno durante el ensayo); se permiten los corticosteroides tópicos o inhalados.
27. Una dosis de metformina que esté fuera del intervalo de dosis especificado para la insuficiencia renal moderada (TFGe 30-59 ml/minuto/1,73m2, fórmula MDRD) de acuerdo con las directrices locales y a juicio del investigador.
28. El tratamiento con cualquier inhibidor de SGLT2 en la inclusión.
29. Antecedentes de cirugía bariátrica o banda gástrica.
30. Administración de sibutramina, fentermina, orlistat, rimonabant, benzfetamina, dietilpropiona, metamfetamina, Victoza (liraglutida) indicado para el tratamiento anti-obesidad y/o fendimetrazina, en los 30 días previos a la firma del consentimiento en la visita 1.
31. Pacientes que, a juicio del investigador, podrían tener riesgo de deshidratación o hipovolemia debido a trastornos coexistentes.
32. Cualquier trastorno que, a juicio del investigador, podría hacer que el paciente fuese incapaz de completar el ensayo o que pudiera exponer al paciente a un riesgo importante.
33. Paciente que abusa en la actualidad del alcohol o de otra drogas o que lo ha hecho en los 6 meses previos a la firma del consentimiento en la visita 1.
34. Implicación en la planificación y/o realización del ensayo (aplicable al personal de AstraZeneca y/o al personal del centro del ensayo).
35. Inclusión previa en el presente ensayo.
36. Participación en otro ensayo clínico con un PI durante los últimos 30 días antes de la firma del consentimiento en la visita 1. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in HbA1c at Week 24 |
| Cambio respecto al momento basal en la HbA1c en la semana 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline to end of treatment |
| Momento basal al final del tratamiento |
|
| E.5.2 | Secondary end point(s) |
1, Percent change from baseline in total body weight at Week 24
2, Change from baseline in FPG at Week 24
3, Change from baseline in seated SBP at Week 24 |
1. Cambio porcentual respecto al momento basal en el peso corporal total en la semana 24.
2. Cambio respecto al momento basal en la GPA en la semana 24
3. Cambio respecto al momento basal en la PAS en sedestación en la semana 24. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline to the end of treatment |
| Momento basal al finalizar el tratamiento. |
|
| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Canada |
| Italy |
| Spain |
| Sweden |
| United States |
|
| E.8.7 | Trial 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
|
| Last Patient Last Visit |
| Última visita del último 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 | 5 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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