A Study of the Safety and Effectiveness of Canagliflozin (JNJ-28431754) in Promoting Weight Loss in Overweight and Obese Patients Who do Not Have Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to test the safety and effectiveness of JNJ-28431754 in promoting weight loss in patients who are overweight or obese and who do not have diabetes.

Detailed Description
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The prevalence of obesity is increasing worldwide. Obesity and being overweight are major risk factors for chronic cardiovascular disease, type 2 diabetes mellitus, hypertension and stroke, and certain types of cancers. JNJ-28431754 is being investigated in this study for its possible effectiveness in promoting weight loss when taken over a 12-week period. The study consists of 3 phases: a pretreatment phase that includes a 7-day screening period and a 4-week run-in period, a 12-week double-blind treatment phase (neither the patient nor the investigator will know which treatment the patient is receiving) with an end-of-treatment visit, and a posttreatment phase. In the pretreatment phase, after giving written informed consent, patients will undergo screening evaluations. Patients who successfully complete the screening period will enter the 4-week run-in period and be given dietary and exercise counseling as standardized non-drug therapy for weight loss. During the 12 weeks of treatment, all patients will continue on the study diet and exercise non-drug therapy and will visit the study site about every 3 weeks to have their weight and the results of other safety and effectiveness tests recorded, and to have blood samples collected to measure the concentration of JNJ-28431754 in their blood. In the posttreatment phase, patients will return to the study site for a follow-up visit 14 days after receiving their last dose of study drug. Patient safety will be monitored throughout the study using spontaneous adverse event reporting, clinical laboratory tests (hematology, serum chemistry, urinalysis); pregnancy tests; physical examinations; electrocardiograms; vital signs measurements; overnight urine collection to measure albumin excretion; assessment of calcium and phosphate homeostasis (balance), bone formation and reabsorption markers, and hormones regulating calcium and phosphorus homeostasis; and self administered vaginal and urine sample collection for fungal and bacterial culture in subjects with symptoms consistent with vulvovaginal candidiasis and urinary tract infection. Patients will complete 2 questionnaires to record their reactions to taking the study drug and the effect of body weight on their daily lives. About 100 patients of the approximately 400 who qualify for the study, and who consent to this, will take part in 2 oral glucose tolerance tests (OGTTs). During the OGTTs they will drink a glucose solution and have a series of blood samples collected to measure glucose concentration, collect their urine over a 2 hour period, and (at the second OGTT only) have blood samples collected to measure JNJ 28431754 blood concentrations. The primary clinical theory for this study is that at well-tolerated doses, JNJ-28431754 is superior to placebo as measured by the percent change in body weight from baseline (Day 1 of the double-blind treatment period) through Week 12.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Ranging Study to Investigate the Safety and Efficacy of JNJ-28431754 in Nondiabetic Overweight and Obese Subjects

Conditions
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Obesity

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI >=30 kg/m2 and <50 kg/m2 or a BMI >=27 kg/m2 and <50 kg/m2 in the presence of controlled hypertension and/or treated or untreated dyslipidemia Must have a stable weight, i.e., increasing or decreasing not more than 5% in the 3 months before screening Serum creatinine <=1.5 mg/dL for men and <=1.4 mg/dL for women at screening Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels within 2 times the upper limit of normal (ULN) and bilirubin within the normal range, unless the findings are consistent with Gilbert's disease fasting plasma glucose PG <7.0 mmol/L (126 mg/dL) at screening Exclusion Criteria: A history of hereditary glucose-galactose malabsorption or primary renal glycosuria An established diagnosis of diabetes mellitus or treatment with glucose lowering drugs at screening A history of reactive hypoglycemia or of symptomatology possibly due to hypoglycemia Fasting triglyceride level >6.78 mmol/L (600 mg/dL) at screening History of obesity with a known cause (e.g., Cushing's disease)

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<br>Each patient will receive 50 mg of canagliflozin (JNJ-28431754) once daily for 12 weeks. | Drug: Canagliflozin (JNJ-28431754)<br>* One 50 mg, 100 mg, or 300 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks.<br>|
| Experimental: Canagliflozin 100 mg<br>Each patient will receive 100 mg of canagliflozin (JNJ-28431754) once daily for 12 weeks. | Drug: Canagliflozin (JNJ-28431754)<br>* One 50 mg, 100 mg, or 300 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks.<br>|
| Experimental: Canagliflozin 300 mg<br>Each patient will receive 300 mg of canagliflozin (JNJ-28431754) once daily for 12 weeks. | Drug: Canagliflozin (JNJ-28431754)<br>* One 50 mg, 100 mg, or 300 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks.<br>|
| Placebo Comparator: Placebo<br>Each patient will receive matching placebo once daily for 12 weeks. | Drug: Placebo<br>* One matching placebo capsule orally once daily for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 group minus placebo) in the least-squares mean percent change. | Day 1 (Baseline) and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the least-squares mean change. | Day 1 (Baseline) and Week 12 | 
| Change in Body Mass Index (BMI) From Baseline to Week 12 | The table below shows the mean change in BMI from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the least-squares mean change. | Day 1 (Baseline) and Week 12 | 
| Percentage of Patients Who Lost at Least 5% of Their Initial Body Weight by Week 12 | The table below shows the percentage of patients who lost at least 5% of their initial body weight by Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo). | Day 1 (Baseline) and Week 12 | 
| Percentage of Patients Who Lost at Least 10% of Their Initial Body Weight by Week 12 | The table below shows the percentage of patients who lost at least 10% of their initial body weight by Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo). | Day 1 (Baseline) and Week 12 | 
| Change in Waist Circumference From Baseline to Week 12 | The table below shows the mean change in waist circumference from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the least-squares mean change. | Day 1 (Baseline) and Week 12 | 
| Change in Hip Circumference From Baseline to Week 12 | The table below shows the mean change in hip circumference from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the least-squares mean change. | Day 1 (Baseline) and Week 12 | 
| Change in Waist/Hip Ratio From Baseline to Week 12 | The table below shows the mean change in waist/hip ratio from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin 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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Obesity, Overweight, Weight loss, Anti-Obesity Agents, Human