E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 10045242 |
E.1.2 | Term | Type II 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 |
Main Study: In subjects with T2DM who have inadequate glycemic control with diet and exercise: • 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.
OBJECTIVES – HIGH GLYCEMIC COHORT SUBSTUDY In subjects with T2DM who have poorer glycemic control (ie, HbA1c >10 and ≤12%) with diet and exercise: After 26 weeks of treatment, to assess the effect of canagliflozin on: • Glycemic control (ie, HbA1c and FPG) • Body weight • Proportion of subjects with HbA1c <7% • Postprandial plasma glucose concentrations (including 1-, and 2-hour PPG and glucose AUC) • Systolic and diastolic blood pressure • Fasting plasma lipids (including LDL-C, HDL-C, total cholesterol, the ratio of LDL C to HDL-C, and triglycerides) • To assess the safety and tolerability of canagliflozin
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E.2.2 | Secondary objectives of the trial |
Main Study: After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on: Fasting plasma glucose (FPG); Proportion of subjects with HbA1c <7% and <6.5%; Body weight; Postprandial plasma glucose concentrations; Systolic and diastolic blood pressure; Fasting plasma lipids; (Fasting measures of beta-cell function. After 52 weeks of treatment, to assess the effect of canagliflozin on: Glycemic control; Body weight; Proportion of subjects with HbA1c <7% and <6.5%; Systolic and diastolic blood pressure; Fasting plasma lipids. After 26 weeks of treatment, in the subset of subjects in the main study who undergo a frequently-sampled (FS) mixed-meal tolerance test (FS-MMTT), to assess the effect of canagliflozin relative to placebo on: Measures of insulin secretion; Measures of insulin sensitivity using a minimal-model-based approach that accounts for UGE. Refer to section 2.1.2 of the protocol for remaining secondary objectives. |
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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 |
The sub-study is described in the protocol, sections 2.3, 4.3, 9.4, and 11.4.5 |
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E.3 | Principal inclusion criteria |
For Main Study: • Man or woman > or =18 and < or =80 years of age with T2DM who meet 1 of the 2 following criteria: – Not on AHA therapy at screening (off for at least 12 weeks) with an HbA1c of > or =7% and < or =10% at the screening (or prescreening) visit (Note: if HbA1c measurement is not within 3 weeks of the Week -2 visit, HbA1c testing must be repeated at the Week -2 visit to assess this inclusion criterion) or – On an oral AHA in monotherapy (except a PPAR gamma agonist, eg, thiazolidinedione [TZD]) or on low-dose combination therapy with metformin (< or =1,000 mg) and SU (at < or =50% of maximally or near maximally effective doses as defined in Attachment 3) with an HbA1c of > or =6.5% and , or =9.5% at the screening (or prescreening) visit and has a Week -2 (after the 8 week diet and exercise/and AHA washout period) HbA1c of > or =7% and < or =10% • 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 criteria. • Site fasting fingerstick glucose of ≥110 mg/dL (6.1 mmol/L) and <270 mg/dL (15 mmol/L) on Day 1. Inclusion Criteria – High Glycemic Cohort Substudy • Man or woman ≥18 and < or =80 years of age with T2DM who meet 1 of the 2 following criteria – Not on AHA therapy at screening (off for at least 12 weeks) with an HbA1c of >10% and < or =12% at the screening (or prescreening) visit (Note: if HbA1c measurement is not within 3 weeks of the Week -2 visit, HbA1c testing must be repeated at the Week -2 visit to assess this inclusion criterion) or – On an oral AHA in monotherapy (except a PPAR gamma agonist, eg, TZD) or on low dose combination therapy with metformin (< or =1,000 mg) and SU (at < or =50% of maximally or near maximally effective doses as defined in Attachment 3) with an HbA1c of > or =6.5% and < or =9.5% at the screening (or prescreening) visit and has a Week -2 visit (after the 8 week diet and exercise and AHA washout period) HbA1c of >10% and < or =12% • FPG < or =350 mg/dL (19.44 mmol/L) at Week -2 visit Note: at the investigator’s discretion, based upon review of recent SMBG values, subjects not meeting this 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 criteria. Inclusion Criteria – Main Study and High Glycemic Cohort Substudy • 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 or 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, consistent with local regulations regarding use of birth control methods for subjects participating in clinical studies, 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 beta human chorionic gonadotropin (beta 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 > or =80% compliance (by pill count) with single-blind placebo capsules.
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E.4 | Principal exclusion criteria |
Main Study and High Glycemic Cohort Substudy Diabetes-related or Metabolic • Repeated FPG and/or fasting SMBG glucose measurements >270 mg/dL (15 mmol/L) during the pretreatment phase, despite reinforcement of diet and exercise counseling. Note: during the single-blind placebo run-in period, subjects eligible for the high glycemic cohort substudy based upon screening visit or Week -2 HbA1c measurement, may continue in the study if their FPG and/or SMBG values are < or =350 mg/dL (19.44 mmol/L) • History of diabetic ketoacidosis, T1DM, pancreas or beta cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy. • Have proliferative diabetic retinopathy for which treatment is planned during the course of the study • History of 1 or more severe hypoglycemic episodes within 6 months before screening. • History of hereditary glucose-galactose malabsorption or primary renal glucosuria • Ongoing, inadequately controlled thyroid disorder (eg, thyroid stimulating hormone [TSH] value that is either <0.2 or >10 mIU/L). • Fasting C-peptide <0.7 pmol/L in subjects for whom the investigator cannot reasonably exclude T1DM based upon clinical evaluation. • On either a PPARgamma agonist (eg, pioglitazone or rosiglitazone), or required ongoing insulin therapy within 12 weeks before 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, 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 5, 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 • Uncontrolled hypertension (ie, using an average of 3 seated blood pressure readings with a diastolic blood pressure > or =100 mmHg or systolic blood pressure > or =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 eGFR <50 mL/min/1.73m2 at screening (provided by the central laboratory) • Fasting serum triglycerides > or =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 (eg, any evidence of active disease within 5 years, or diagnosis of malignancy within this period) Note: subjects with squamous or basal cell carcinomas of the skin carcinomas 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 may participate. • Clinically important hematologic disorder • 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 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 • Current use of a disallowed therapy: – Any other SGLT2 inhibitor – Antihyperglycemic agents except as indicated in the study inclusion criteria – Digoxin • Subjects receiving anti-hypertensive or anti-hyperlipidemic 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 (refer to Section 14.1 in the protocol, Physical Description of Study Drug[s]) • Contraindication to the use of sitagliptin (per local prescribing information) Please refer to the protocol, section 4.3, for the remaining criteria.
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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 through Week 26. The LOCF method will be applied when the Week 26 values are missing. In subjects receiving rescue therapy, their measurements made before rescue will be used as the last observations. An analysis of covariance (ANCOVA) model with treatment and stratification factor(s)as fixed effects and HbA1c baseline value as covariate will be used in the main study. The treatment difference (canagliflozin minus placebo) in the least squares means and the 2-sided 95% CI will be estimated based on this model. Sensitivity analyses will be conducted to assess the robustness of the primary analysis to the effect of rescue medication. As a supportive analysis, change from baseline in HbA1c will be analyzed using a repeated measures model based on the restricted maximum likelihood (REML). The analysis will be based on observed data and will include the fixed, categorical effects of treatment, stratification factor(s), visit, and treatment by-visit interaction, as well as the continuous, fixed covariates of baseline and baseline-by-visit interaction. An unstructured covariance will be used to model the within-patient errors. The treatment comparisons will be made between each of the canagliflozin treatments and placebo at Week 26 and significance tests will be based on the difference of the least squares means.
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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 | Yes |
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 | 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
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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 | 40 |
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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Definition of end of trial is provided in Section 17.9.2 of Protocol . |
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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 | 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 |