| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Monotherapy |
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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 | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
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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 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 |
• Fasting plasma glucose (FPG)
• Body weight
• Proportion of subjects with HbA1c <7.0% and <6.5%
• 2 hour postprandial plasma glucose (2 h PPG) after a standard meal
• 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)
• Systolic and diastolic blood pressure
• Time to rescue therapy and proportion of subjects receiving rescue therapy
• Fasting measure of beta-cell function (ie, HOMA-B)
After 52 weeks of treatment, to assess the effect of canagliflozin relative to sitagliptin on:
• Glycemic control (HbA1c and FPG)
• Body weight
• Proportion of subjects with HbA1c <7.0% and <6.5%
• Fasting plasma lipids (ie, LDL-C, HDL-C, total cholesterol, LDL-C to HDL-C ratio, and triglycerides)
• Systolic and diastolic blood pressure...
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Man or woman ≥18 and ≤80 years of age with T2DM who meet 1 of the following 4 criteria:
On metformin IR monotherapy at a stable protocol-specified dose* for at least 8 weeks before screening and has an HbA1c of ≥7.0% and ≤10.5% at screening (or at Week -2, if screening measurement is more than 3 weeks before Week -2)
or
– On metformin ER monotherapy at a protocol-specified dose* with an HbA1c of ≥7.0% and ≤10.5% at screening and has a Week -2 visit HbA1c of ≥7.0% and ≤10.5%, after at least 8 weeks on a stable protocol-specified dose* of metformin IR
or
– On metformin monotherapy (IR or ER) at a dose <2,000 mg/day with an HbA1c of ≥7.5% and ≤11.0% at screening and has a Week -2 visit HbA1c of ≥7.0% and ≤10.5%, after at least 8 weeks on a stable protocol-specified dose* of metformin IR
or
On metformin (IR or ER) in combination with an SU with an HbA1c of ≥6.5% and ≤9.5% at screening and has a Week -2 visit HbA1c of ≥7.0% and ≤10.5%, after at least 8 weeks on a stable protocol-specified dose* of metformin IR
* Protocol-specified dose of metformin: ≥2,000 mg/day (or ≥1,500 mg/day, if unable to tolerate a higher dose)
• FPG <270 mg/dL (15 mmol/L) at Week -2.
Note: at the investigator’s discretion, based upon review of recent SMBG values, subjects not meeting the Week -2 FPG criterion may return to the investigational site within 7 days for a one-time repeat FPG and continue in the study if the subject’s repeat FPG meets the criterion.
• Site fasting fingerstick glucose of ≥110 mg/dL (6.1 mmol/L) and <270 mg/dL (15 mmol/L) on Day 1
Note: at the investigator’s discretion, based upon review of recent SMBG values, subjects not meeting the Day 1 criterion may return to the investigational site within 7 days for a one-time repeat fingerstick glucose and continue in the study if the subject’s repeat fingerstick glucose meets the criterion.
• 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
Note: subjects who are not heterosexually active at screening must agree to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study.
• 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 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
•Ongoing, inadequately controlled thyroid disorder (eg, subject has a known thyroid stimulating hormone [TSH] value that is either <0.2 or >10 mIU/L)
•On either a PPARγ agonist (eg, a thiazolidinedione (TZD) [pioglitazone or rosiglitazone]) ongoing insulin therapy, another SGLT2 inhibitor, or any other AHA
(including agents such as colesevelam and bromocriptine that have indications in
some regions for treatment of T2DM) except as specified in the study inclusion
criteria within 12 weeks before the screening visit
•Ongoing eating disorder or significant weight loss or weight gain within 12 weeks before the screening visit, 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
•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) <55 mL/min/1.73 m2
(or <60 mL/min/1.73 m2 if based upon restriction of metformin use in the metformin
local label) 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
•Investigator’s assessment that the subject’s life expectancy is less than 1 year
•Any condition that in the opinion of the investigator would make participation not in the best interest of the subject, or could prevent, limit, or confound the protocol-specified assessments
•Major surgery (ie, requiring general anesthesia) within 12 weeks before screening, or has not fully recovered from surgery, or planned surgery during the time the subject is expected to participate in the study
Medications/Therapies
•Subjects receiving antihypertensive or antihyperlipidemic therapy not on a stable regimen (same medication and dose[s]) for at least 4 weeks before Day 1
•Known allergies, hypersensitivity, or intolerance to canagliflozin or its excipients
•Contraindication to the use of metformin or sitagliptin (per local prescribing information[ie, local label])
•Current use of a corticosteroid medication or immunosuppressive agent, or likely to require treatment with a corticosteroid medication (for longer than 2 weeks in duration) or an immunosuppressive agent
•Received an investigational drug (including vaccines), other than a placebo agent, or used an investigational medical device within 3 months...
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the change in HbA1c from baseline to 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 | 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 | 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 | Yes |
| E.8.2.3 | Other | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| 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
|
| last visit of the last subject |
|
| 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 | 4 |
| 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 | 4 |
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