A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects With Type 2 Diabetes Mellitus

Study Objective

Primary Objectives

In subjects with type 2 diabetes mellitus (T2DM), with inadequate glycemic control, who have a history or high risk of CV disease:

• to assess the effect of canagliflozin plus standard of care relative to placebo plus standard of care on CV risk as measured by the hazard ratio (HR) for a composite endpoint (MACE including CV death, nonfatal MI, and nonfatal stroke)
• to assess the safety and tolerability of canagliflozin plus standard of care relative to placebo plus standard of care

Secondary Objectives

In subjects with T2DM, with inadequate glycemic control, who have a history or high risk of CV disease:

• to assess the effect of canagliflozin plus standard of care relative to placebo plus standard of care on:
  • fasting measures of beta-cell function (homeostasis model assessment [HOMA]-B and the proinsulin/insulin ratio)
  • the proportion of subjects with progression of albuminuria (progression defined as ≥1 step increase, ie, no albuminuria to micro- or macro-albuminuria or from micro-albuminuria to macro-albuminuria)
  • the urinary albumin/creatinine ratio
  • renal function (as measured by the change from baseline in estimated glomerular filtration rate [eGFR])

• to assess the effect of canagliflozin relative to placebo after 18 weeks and at the end of the treatment period on:
  • glycemic efficacy (HbA1c and FPG)
  • body weight
  • blood pressure (systolic and diastolic)
  • fasting plasma lipids (triglycerides, HDL-C, low-density lipoprotein cholesterol [LDL-C], total cholesterol, and the ratio of LDL-C to HDL-C)

Participation conditions

Inclusion Criteria at Screening Visit

• Man or woman with a diagnosis of T2DM with HbA1c level ≥7.0% to ≤10.5% at screening and be either (1) not currently on AHA therapy or (2) on AHA monotherapy or combination therapy with any approved class of agents: eg, sulfonylurea, metformin, PPARγ agonist, alpha-glucosidase inhibitor, GLP-1 analogue, DPP-4 inhibitor, or insulin.
• History or high risk of CV disease defined on the basis of either:
  • Age ≥30 years with documented symptomatic atherosclerotic CV disease: including stroke; MI; hospital admission for unstable angina; coronary artery bypass graft; percutaneous coronary intervention (with or without stenting); peripheral revascularization (angioplasty or surgery); symptomatic with documented hemodynamically-significant carotid or peripheral vascular disease; or amputation secondary to vascular disease
  • Age ≥50 years with 2 or more of the following risk factors determined at the screening visit: duration of T2DM of 10 years or more, systolic blood pressure >140 mmHg (average of 3 readings) recorded at the Screening Visit, while the subject is on at least one blood pressure-lowering treatment, current daily cigarette smoker, documented micro- or macro-albuminuria, or documented HDL-C of <1 mmol/L (<39 mg/dL).
     
• 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 less than 18 months and a serum follicle stimulating hormone (FSH) level >40 IU/mL, or
  • surgically sterile (have had a hysterectomy or bilateral oophorectomy, 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 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.
• 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. Refusal to give consent for this component does not exclude a subject from participation in the clinical study.

Exclusion Criteria

Potential subjects who meet any of the following criteria will be excluded from participating in the study:

Diabetes-Related/Metabolic

• History of diabetic ketoacidosis, T1DM, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy
• On an AHA and not on a stable regimen (ie, agents and doses) for at least 8 weeks before the screening visit and through the screening/run-in period
• Fasting fingerstick glucose at site >270 mg/dL (>15 mmol/L) at Baseline/Day 1
• For patients on a sulphonylurea agent or on insulin: fasting fingerstick glucose at site <110 mg/dL (<6 mmol/L) at Baseline/Day 1
• History of one 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.

Renal/Cardiovascular

• 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.
• Myocardial infarction, unstable angina, revascularization procedure, or cerebrovascular accident within 3 months before screening, or a planned revascularization procedure, or history of New York Heart Association (NYHA) Class 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)

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
• Any history of or planned bariatric surgery

Laboratory

• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 at screening
• For subjects taking metformin: at screening, serum creatinine ≥1.4 mg/dL (124 μmol/L) for men or ≥1.3 mg/dL (115 μmol/L) for women; no contraindication to the use of metformin (including eGFR) based on the label of the country of investigational site
• ALT levels >2.0 times the ULN or total bilirubin >1.5 times the ULN at screening, unless in the opinion of the investigator and as agreed upon by the sponsor’s medical officer, the findings are consistent with Gilbert’s disease

Other conditions

• History of malignancy within 5 years before screening (exceptions: squamous and basal cell carcinomas of the skin and carcinoma of the cervix in situ, 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)
• History of human immunodeficiency virus (HIV) antibody positive
• Subject has a current clinically important hematological disorder (eg, symptomatic anemia, proliferative bone marrow disorder, and thrombocytopenia)
• Investigator’s assessment that the subject’s life expectancy is less than 1 year, or 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 safety or efficacy assessments
• Major surgery (ie, requiring general anesthesia) within 3 months of the screening visit or any surgery planned during the subject’s expected participation in the study (except minor surgery, ie, outpatient surgery under local anesthesia)
• Any condition that, in the opinion of the investigator, would compromise the well being of the subject or prevent the subject from meeting or performing study requirements

Centre Hospitalier de Luxembourg