| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with T2DM with inadequate glycemic control on a maximally effective dose of metformin in monotherapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 diabetes with inadequate glucose control on metformin |
|
| 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 | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10063624 |
| E.1.2 | Term | Type II diabetes mellitus inadequate control |
| 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 |
After 18 weeks of treatment:
-To assess the effect of canagliflozin 150 mg administered twice daily on HbA1c relative to placebo
- To assess the safety and tolerability of canagliflozin |
|
| E.2.2 | Secondary objectives of the trial |
After 18 weeks of treatment:
- To assess the effect of canagliflozin 50 mg administered twice daily on HbA1c relative to placebo
- To assess the effect of canagliflozin 150 mg administered twice daily, or canagliflozin 50 mg
administered twice daily, on the following parameters relative to placebo:
– Fasting plasma glucose (FPG)
– Body weight
– Proportion of subjects with HbA1c <7.0% and <6.5%
– 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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Be a man or woman ≥18 and ≤80 years of age with T2DM and on metformin monotherapy at a stable protocol-specified dose (≥2,000 mg/day [or ≥1,500 mg/day, if unable to tolerate a higher dose]) for at least 8 weeks immediately prior to screening and have 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)
2. 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.
3. Fasting fingerstick glucose of ≥110 mg/dL (6.1 mmol/L) and <270 mg/dL (15 mmol/L)
performed at home (with documentation of the value in the subject's diary) or at the investigational site 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 the assessment of a one-time repeat fingerstick glucose (performed at home or at the investigational site) and continue in the study if the subject’s repeat fingerstick glucose
meets the criterion.
4. 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.
5. Women of childbearing potential must have a negative urine β-human chorionic gonadotropin (β-hCG) pregnancy test at screening and baseline (predose, Day 1)
6. Willing and able to adhere to the prohibitions and restrictions specified in this protocol
7. 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
8. Adequate compliance with the run-in period study procedures, including performance of the fasting SMBG measurements (completed at least 3 or more fasting SMBG measurements per week) with appropriate diary entries, and ≥80% compliance (by pill count) with singleblind placebo capsules |
|
| E.4 | Principal exclusion criteria |
Diabetes-related or Metabolic
1. Has a history of diabetic ketoacidosis, T1DM, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy
2. Has 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
3. Has proliferative diabetic retinopathy for which treatment is planned during the course of the study
4. Has a history of 1 or more severe hypoglycemic episode within 6 months before screening
Note: a severe hypoglycemic episode is defined as an event that requires the help of another person.
5. Has history of hereditary glucose-galactose malabsorption or primary renal glucosuria
6. Has ongoing, inadequately controlled thyroid disorder (eg, subject has a known thyroid stimulating hormone [TSH] value that is either <0.2 or >10 mIU/L)
Note: subjects on thyroid hormone replacement therapy must be on stable doses for at least 6 weeks prior to Day 1
7. Is on either a PPARγ agonist (eg, a thiazolidinedione (TZD) [pioglitazone or rosiglitazone]), ongoing insulin therapy, another SGLT2 inhibitor, or any AHA (including agents such as colesevelam and bromocriptine that have indications in some regions for treatment of
T2DM) other than metformin, as specified in the study inclusion criteria, within 12 weeks before the screening visit
Note: subjects who have been treated with only a single dose of insulin may participate.
8. Has 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
9. Has renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant.
Note: subjects with a history of treated childhood renal disease, without sequelae, may participate.
10. 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
11. Has findings on 12-lead ECG that would require urgent diagnostic evaluation or intervention (eg, new clinically important arrhythmia or conduction disturbance)
12. 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.
Note: subjects may have their blood pressure lowering medication regimen adjusted and be re-evaluated to assess this criterion (on a stable regimen for at least 4 weeks before Day 1 to be eligible).
Gastrointestinal
13. Has 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.
14. Has history of prior bariatric surgical procedure within 3 years before the screening visit.
Note: subjects with bariatric surgery more than 3 years prior to screening must be at a stable weight to be eligible to participate.
Laboratory
15. Estimated glomerular filtration rate (eGFR) (as determined by central laboratory)
<55 mL/min/1.73 m2 (or eGFR <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
Note: For the purpose of the above eGFR exclusion criterion, a central laboratory report of eGFR<60 mL/min/1.73 m2 will be considered equivalent to a creatinine clearance (CrCl) <60 mL/min in cases where the restriction of metformin use in the metformin local label is
based upon CrCl. A one-time repeat measurement of eGFR is allowed, at the discretion of the investigator, if the values for serum creatinine/eGFR are not consistent with prior values.
16. Fasting serum triglycerides ≥600 mg/dL (6.74 mmol/L) at screening (or subsequent visit if not fasting at screening)
Note: a one-time repeat of the serum triglycerides is allowed, at the discretion of the investigator, if the screening value is not consistent with recent values.
17. Has an ALT 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
18. History of malignancy within 5 years before screening (eg, any evidence of active disease within 5 years, or diagnosis of malignancy within this period).
...See protocol for entire list |
|
| 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 18. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints will include the change from baseline to Week 18 in FPG, and percent change to Week 18 from baseline in body weight. The proportion of subjects with HbA1c <7.0%
at Week 18 will also be a key secondary endpoint.
Additional efficacy endpoints will include change in fasting lipid profile and in systolic and diastolic blood pressure at Weeks 18. Proportion of subjects with HbA1c <6.5% at Week 18 will
also be an endpoint of interest. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Mexico |
| Russian Federation |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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