An Efficacy, Safety, and Tolerability Study of Canagliflozin (JNJ-28431754) in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness, safety, and tolerability of JNJ-28431754 compared with placebo in patients with type 2 diabetes.

Detailed Description
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Type 2 diabetes mellitus is a metabolic disorder that is characterized by decreased secretion of insulin by the pancreas and resistance to the action of insulin in various tissues (muscle, liver, and adipose), which results in impaired glucose uptake. Chronic hyperglycemia leads to progressive impairment of insulin secretion and to insulin resistance of peripheral tissues in diabetes (so-called glucose toxicity), which further worsens control of blood glucose. In addition, chronic hyperglycemia is a major risk factor for complications, including heart disease, retinopathy, nephropathy, and neuropathy. Although numerous treatments have been developed for the treatment of diabetes and individual agents may be highly effective for some patients, it is still difficult to maintain optimal glycemic control in most patients with diabetes. This is a randomized, double-blind, placebo-controlled, parallel group, multicenter, dose-ranging study to determine the efficacy, safety and tolerability of JNJ-28431754 taken orally over 12 weeks, compared with placebo, in the treatment of Type 2 diabetes mellitus. The primary clinical hypothesis is that JNJ-28431754 is superior to placebo as measured by the change in hemoglobin A1c from baseline through Week 12 in the treatment of type 2 diabetes mellitus. Subject safety will be monitored throughout the study using spontaneous adverse event reporting, clinical laboratory tests (hematology, serum chemistry, urinalysis); severe and serious hypoglycemic episodes, assessment of urinary albumin excretion and markers of proximal renal tubular function; pregnancy tests; electrocardiograms (ECGs); vital sign measurements; physical examinations, assessment of calcium and phosphate homeostasis, bone formation and resorption markers, and hormones regulating calcium and phosphorus homeostasis; and vaginal and urine sample collection for fungal and bacterial culture in subjects with symptoms consistent with vulvovaginal candidiasis (VVC) or urinary tract infection (UTI).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Double-Dummy, Parallel Group, Multicenter, Dose-Ranging Study in Subjects With Type 2 Diabetes Mellitus to Evaluate the Efficacy, Safety, and Tolerability of Orally Administered SGLT2 Inhibitor JNJ-28431754 With Sitagliptin as a Reference Arm

Conditions
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Diabetes Mellitus, Type II, Diabetes Mellitus, Non Insulin Dependent

Intervention / Treatment
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* Drug: Canagliflozin (JNJ-28431754)
* Drug: Sitagliptin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a diagnosis of type 2 diabetes mellitus Hemoglobin A1c levels >=7% and <=10.5% taking a stable daily dose of metformin Body mass index (BMI) 25 to 45 kg/m2 except those of Asian descent who must have a BMI of 24 to 45 kg/m2 Stable body weight Serum creatinine <=1.5 mg/dL (132.6 umol/L) for men and <=1.4 mg/dL (123.76 umol/L) for women Exclusion Criteria: Patients must not have prior exposure or known contraindication or suspected hypersensitivity to canagliflozin (JNJ-28431754) Known contraindication or suspected hypersensitivity to sitagliptin or metformin A history of diabetic ketoacidosis or type 1 diabetes mellitus History of pancreas or beta-cell transplantation History of active proliferative diabetic retinopathy History of hereditary glucose-galactose malabsorption or primary renal glucosuria

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Canagliflozin 50 mg daily<br>Each patient will receive 50 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). | Drug: Canagliflozin (JNJ-28431754)<br>* One 50 mg, 100 mg, 200 mg, or 300 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks or one 300 mg over-encapsulated tablet orally twice daily for 12 weeks.<br>* Other names: JNJ-28431754;Drug: Placebo<br>* One matching placebo capsule orally (by mouth) once or twice daily for 12 weeks.<br>|
| Experimental: Canagliflozin 100 mg daily<br>Each patient will receive 100 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). | Drug: Canagliflozin (JNJ-28431754)<br>* One 50 mg, 100 mg, 200 mg, or 300 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks or one 300 mg over-encapsulated tablet orally twice daily for 12 weeks.<br>* Other names: JNJ-28431754;Drug: Placebo<br>* One matching placebo capsule orally (by mouth) once or twice daily for 12 weeks.<br>|
| Experimental: Canagliflozin 200 mg daily<br>Each patient will receive 200 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). | Drug: Canagliflozin (JNJ-28431754)<br>* One 50 mg, 100 mg, 200 mg, or 300 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks or one 300 mg over-encapsulated tablet orally twice daily for 12 weeks.<br>* Other names: JNJ-28431754;Drug: Placebo<br>* One matching placebo capsule orally (by mouth) once or twice daily for 12 weeks.<br>|
| Experimental: Canagliflozin 300 mg daily<br>Each patient will receive 300 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo capsule once daily (in the evening). | Drug: Canagliflozin (JNJ-28431754)<br>* One 50 mg, 100 mg, 200 mg, or 300 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks or one 300 mg over-encapsulated tablet orally twice daily for 12 weeks.<br>* Other names: JNJ-28431754;Drug: Placebo<br>* One matching placebo capsule orally (by mouth) once or twice daily for 12 weeks.<br>|
| Experimental: Canagliflozin 300 mg twice daily<br>Each patient will receive 300 mg of canagliflozin (JNJ-28431754) twice daily for 12 weeks. | Drug: Canagliflozin (JNJ-28431754)<br>* One 50 mg, 100 mg, 200 mg, or 300 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks or one 300 mg over-encapsulated tablet orally twice daily for 12 weeks.<br>* Other names: JNJ-28431754;|
| Active Comparator: Sitagliptin 100 mg daily<br>Each patient will receive 100 mg of sitagliptin once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). | Drug: Sitagliptin<br>* One 100 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks.<br>Drug: Placebo<br>* One matching placebo capsule orally (by mouth) once or twice daily for 12 weeks.<br>|
| Placebo Comparator: Placebo<br>Each patient will receive matching placebo twice daily for 12 weeks. | Drug: Placebo<br>* One matching placebo capsule orally (by mouth) once or twice daily for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to Week 12 | The table below shows the mean change in HbA1c from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin or sitagliptin group minus placebo) in the least-squares mean change. | Day 1 (Baseline) and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 12 | The table below shows the mean change in FPG from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin or sitagliptin group minus placebo) in the least-squares mean change. | Day 1 (Baseline) and Week 12 | 
| Percentage of Patients With Symptoms of Hypoglycemia | The table below shows the percentage of patients who experienced symptomatic hypoglycemic events between Baseline and Week 12. | Up to Week 12 | 
| Change in Overnight Urine Glucose/Creatinine Ratio From Baseline to Week 12 | The table below shows the mean change in overnight urine glucose/creatinine ratio from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin or sitagliptin group minus placebo) in the least-squares mean change. | Day 1 (Baseline) and Week 12 | 
| Absolute Change in Body Weight From Baseline to Week 12 | The table below shows the mean absolute change in body weight from Baseline to Week 12 for each treatment group. | Day 1 (Baseline) and Week 12 | 
| Percent Change in Body Weight From Baseline to Week 12 | The table below shows the mean percent change in body weight from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin or sitagliptin group minus placebo) in the least-squares mean change. | Day 1 (Baseline) and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, Metformin, Hemoglobin A1c