| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus with inadeguate glycemic control |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
|
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
| After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on: Fasting plasma glucose (FPG); Body weight; Proportion of subjects with HbA1c <7.0% and <6.5% ; Fasting plasma lipids; Fasting measures of beta cell function; Systolic and diastolic blood pressure; Time to rescue therapy and proportion of subjects receiving rescue therapy After 52 weeks of treatment, to assess the effect of canagliflozin relative to baseline on: Glycemic control; Body weight; Proportion of subjects with HbA1c <7.0% and <6.5%; Fasting plasma lipids; Fasting measures of beta cell function; Systolic and diastolic blood pressure; Time to rescue therapy and proportion of subjects receiving rescue therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Potential subjects must satisfy all of the following criteria at screening, or at the indicated visits, to be enrolled in the study: • Man or woman ≥18 and ≤80 years of age with T2DM who meets 1 of the following 5 criteria: - On dual combination metformin and pioglitazone, both agents at protocol-specified doses* (stable doses for at least 16 weeks prior to screening), with an HbA1c of ≥7.0% and ≤10.5% at screening (or at Week -2, if screening measurement is more than 3 weeks prior to Week -2) or - On dual combination metformin and pioglitazone (stable doses for at least 8 weeks prior to screening), with either agent at a dose below protocol-specified*, with an HbA1c of ≥7.5 % and ≤11.0% at screening, and has an HbA1c of ≥7.0% and ≤10.5% at Week -2, after at least 8 weeks on stable protocol-specified* doses of metformin and pioglitazone or - On dual combination metformin and rosiglitazone, with an HbA1c of ≥7.0% and ≤10.5% at screening (stable doses for at least 8 weeks prior to screening), and has an HbA1c of ≥7.0% and ≤10.5% at Week -2, after at least 8 weeks on stable protocol-specified* doses of metformin and pioglitazone Canagliflozin: Clinical Protocol 28431754DIA3012 FINAL - 08 January 2010 55 or - On a PPARγ agent (pioglitazone or rosiglitazone) in dual combination with another oral AHA, with an HbA1c of ≥7.0% and ≤10.5% at screening (stable doses for at least 8 weeks prior to screening), and has an HbA1c of ≥7.0% and ≤10.5% at Week -2, after at least 8 weeks on stable protocol-specified* doses of metformin and pioglitazone or - On metformin, a PPARγ agent (pioglitazone or rosiglitazone), and an SU or a DPP-4 inhibitor in triple combination therapy with an HbA1c of ≥6.5% and ≤9.5% at screening (stable doses for at least 8 weeks prior to screening), and has an HbA1c of ≥7.0% and ≤10.5% at Week -2, after at least 8 weeks on stable protocolspecified* doses of metformin and pioglitazone *Protocol-specified doses = metformin ≥2,000 mg per day (or ≥1,500 mg per day, if unable to tolerate a higher dose) and pioglitazone 30 mg or 45 mg per day. • 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. • 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 Canagliflozin: Clinical Protocol 28431754DIA3012 FINAL - 08 January 2010 56 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. |
|
| E.4 | Principal exclusion criteria |
| Diabetes-related or Metabolic • History of diabetic ketoacidosis, T1DM, pancreas or β-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 during the pre-treatment 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 Canagliflozin: Clinical Protocol 28431754DIA3012 FINAL - 08 January 2010 57 • Ongoing, inadequately controlled thyroid disorder (eg, thyroid stimulating hormone [TSH] value <0.2 or >10 mIU/L); • Required ongoing insulin therapy within 12 weeks prior to the screening visit • 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. • 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 • Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or serum creatinine ≥1.4 mg/dL (124 μmol/L) for men and ≥1.3 mg/dL (115 μmol/L) for women • 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) Other conditions • History of malignancy within 5 years before screening (exceptions: squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or a malignancy that in the opinion of the investigator, with concurrence with the sponsor’s medical monitor, is considered cured with minimal risk of recurrence) • Clinically important hematologic disorder (eg, symptomatic anemia, proliferative bone marrow disorder, thrombocytopenia) • History of human immunodeficiency virus (HIV) antibody positive |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy endpoint: change in HbA1c from baseline to Week 26. |
|
| 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 | 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 | 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 | Yes |
| 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 |
|
| 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 | 4 |
| 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 |
|
| 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
| |
| 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 | 0 |
| 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 |
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