E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes Mellitus with moderate renal impairmnet |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045250 |
E.1.2 | Term | Type II diabetes mellitus with renal manifestations |
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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 assess the effect of canagliflozin relative to placebo on hemoglobin A1c (HbA1c) after 26 weeks of treatment To assess the safety and tolerability of canagliflozin |
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E.2.2 | Secondary objectives of the trial |
After 26 weeks of treatment, to assess the effects of canagliflozin relative to placebo on: Fasting plasma glucose (FPG) Proportion of subjects with an HbA1c<7% Systolic and diastolic blood pressure Proportion of subjects receiving rescue therapy and time to rescue therapy Fasting plasma lipids (ie, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol, LDL-C to HDL-C ratio, and triglycerides) Body weight Renal function (eGFR and ACR) After 52 weeks of treatment, to assess the effect of canagliflozin relative to placebo on: Glycemic control (HbA1c and FPG) Proportion of subjects with HbA1c <7% Systolic and diastolic blood pressure Proportion of subjects receiving rescue therapy and time to rescue therapy Fasting plasma lipids (ie, LDL-C, HDL-C, total cholesterol, LDL-C to HDL-C ratio, and triglycerides) Body weight. Renal function (eGFR and ACR) |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
ALTRI SOTTOSTUDI: su un sottogruppo di ca. 90 soggetti verra` condotto un sottostudio: raccolta delle urine delle 24 ore per misurare i valori di creatinina, albumina e glicemia
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E.3 | Principal inclusion criteria |
Potential subjects must satisfy all of the following criteria to be enrolled in the study: Man or woman with T2DM, age ≥25 years, and either not on an AHA or on any AHA in monotherapy or combination therapy (including oral or non-oral agents). HbA1c ≥7.0% to ≤10.5% at screening and Week -2 visits. On a stable AHA regimen consistent with local prescribing information (ie, local label[s]) for at least 8 weeks (and 12 weeks for PPARγ agents [eg, rosiglitazone or pioglitazone]) before Week -2. Have moderate renal impairment, as defined by eGFR values (estimated by the 4-variable MDRD equation) ≥30 and <50 mL/min/1.73 m2 at both the screening and the Week -2 visit, with generally stable renal function, as demonstrated by ≤25% decline in eGFR at Week-2 relative to the screening visit value FPG ≤270 mg/dL (15 mmol/L) at Week -2 Site fasting fingerstick glucose of ≥110 mg/dL (6.1 mmol/L) and ≤270 mg/dL (15 mmol/L) on Day 1 Canagliflozin: Clinical Protocol 28431754DIA3004 Women must be: postmenopausal, defined as ◊ >45 years of age with amenorrhea for at least 18 months, or ◊ >45 years of age with amenorrhea for at least 6 months and <18 months and a serum follicle stimulating hormone (FSH) level >40 IU/mL, or surgically sterile (have had a hysterectomy, bilateral oophorectomy, or tubal ligation) or otherwise be incapable of pregnancy, or heterosexually active and practicing a highly effective method of birth control, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (eg, condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization, and consistent with local regulations regarding use of birth control methods for subjects participating in clinical trials, for the duration of their participation in the study, or not heterosexually active. Women of childbearing potential must have a negative urine β-human chorionic gonadotropin (β-hCG) pregnancy test at screening and baseline (predose, Day 1). Willing and able to adhere to the prohibitions and restrictions specified in this protocol. Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. To participate in the optional pharmacogenomic component of this study, subjects must have signed the informed consent form for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study (where local regulations permit). Refusal to give consent for this component does not exclude a subject from participation in the clinical study. Adequate compliance with the run-in period study procedures, including performance of the SMBG measurements (completed at least 3 or more SMBG measurements per week) with appropriate diary entries, and ≥80% compliance (by pill count) with single-blind placebo capsules. |
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E.4 | Principal exclusion criteria |
Diabetes-related or Metabolic History of diabetic ketoacidosis, T1DM, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy Repeated (ie, 2 or more over a 1-week period) FPG and/or fasting SMBG glucose measurements >270 mg/dL (15 mmol/L) during the pretreatment phase, despite reinforcement of diet and exercise counseling Have proliferative diabetic retinopathy for which treatment is planned during the course of the study History of 1 or more severe hypoglycemic episode within 6 months before screening. History of hereditary glucose-galactose malabsorption or primary renal glucosuria Ongoing, inadequately controlled thyroid disorder (eg, subject has a known thyroid stimulating hormone [TSH] value that is either <0.2 or >10 mIU/L) Ongoing eating disorder or significant weight loss or weight gain within 12 weeks, defined as an increase or decrease of 5% in body weight based upon clinic-based measurement or, if not available, subject report Renal/Cardiovascular Renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant Presence of nephrotic syndrome (eg, severe proteinuria with hypoalbuminemia and/or edema), or inflammatory renal disease (eg, acute interstitial nephritis, acute or rapidly-progressive glomerulonephritis) Subject is likely to require dialysis or transplantation during participation in the study Myocardial infarction, unstable angina, revascularization procedure (eg, stent or bypass graft surgery), or cerebrovascular accident within 3 months before screening, or revascularization procedure is planned, or subject has a history of New York Heart Association (NYHA) Class III-IV cardiac disease (refer to Attachment 3, New York Heart Association Classification of Cardiac Disease, for a description of the classes) Findings on 12-lead ECG that would require urgent diagnostic evaluation or intervention (eg, new clinically important arrhythmia or conduction disturbance) Uncontrolled hypertension (ie, using an average of 3 seated blood pressure readings with a diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) at Week -2 Gastrointestinal History of hepatitis B surface antigen or hepatitis C antibody positive (unless associated with documented persistently stable/normal range aspartate aminotransferase [AST] and ALT levels), or other clinically active liver disease History of prior bariatric surgical procedure within 3 years before the screening visit Laboratory Fasting serum triglycerides ≥600 mg/dL (6.74 mmol/L) at screening (or subsequent visit if not fasting at screening) Alanine aminotransferase level >2.0 times the ULN or total bilirubin >1.5 times the ULN at screening (for elevations in bilirubin: if, in the opinion of the investigator and agreed upon by the sponsor s medical officer, the elevation in bilirubin is consistent with Gilbert s disease, the subject may participate) Hemoglobin concentration <10 g/L at screening |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the change in The primary efficacy endpoint will be the change in HbA1c from baseline through Week 26.</ |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
- same IMP used at different dosage |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 |
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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
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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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |