E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes Mellitus with Moderate Renal Impairment |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062237 |
E.1.2 | Term | Renal impairment |
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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 |
In subjects with inadequately-controlled T2DM and moderate renal insufficiency: • 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; Body weight, and 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; Body weight; Renal function (eGFR and ACR)
Over 26 weeks of treatment, to assess exposure-response relationships of canagliflozin using a population pharmacokinetic (PK) approach.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Man or woman with T2DM, age > or =25 years, and either not on an AHA or on any AHA in monotherapy or combination therapy (including oral or non-oral agents). • HbA1c > or =7.0% to < or =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 PPARgamma agents [eg, rosiglitazone or pioglitazone]) before Week -2. Note: a stable dose of insulin is defined as no change in the insulin regimen (ie, type[s] of insulin) and < or =15% change in the average total daily dose of insulin (ie, averaged over 7 days to account for day to day variability, changes < or =15% over the preceding 8 weeks). • Have moderate renal impairment, as defined by eGFR values (estimated by the 4 variable MDRD equation) > or =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 < or =25% decline in eGFR at Week-2 relative to the screening visit value • FPG < or =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 criteria 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 > or =110 mg/dL (6.1 mmol/L) and < or =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 criteria 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. The site should complete the fingerstick glucose determination at Day 1 prior to conducting other visit procedures. • 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 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 |
Diabetes-related or Metabolic • History of diabetic ketoacidosis, T1DM, pancreas or beta cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy • 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 • 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 • 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, or inflammatory renal disease • Subject is likely to require dialysis or transplantation during participation in the study • 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 • Findings on 12-lead ECG that would require urgent diagnostic evaluation or intervention • Uncontrolled hypertension 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 > 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) • Hemoglobin concentration <10 g/L at screening 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 • 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 subject has not fully recovered from surgery, or planned surgery during time the subject is expected to participate in the study Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate Medications/Therapies • Current use of a disallowed therapy: – Any other SGLT2 inhibitor – Colesevelam and bromocriptine • 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 protocol, Physical Description of Study Drugs) • 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 Note: subjects using inhaled, intranasal, intra-articular, or topical corticosteroids, or corticosteroids in therapeutic replacement doses may participate • Subject currently treated with or who are likely to require treatment with a non steroidal anti-inflammatory drug (NSAID) in higher doses during their expected participation in the study • Received an investigational drug (including vaccines), other than a placebo agent, or used an investigational medical device within 3 months before the planned start of treatment or received at least 1 dose of canagliflozin in a prior study General • History of drug or alcohol abuse within 3 years before screening • Pregnant or breast-feeding or planning to become pregnant or breast-feed during the study
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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. |
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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 | 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
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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The end of the trial is 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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 24 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 26 |