Diabetes Mellitus, Type II, Diabetes Mellitus, Non Insulin Dependent
Conditions
Keywords
Type 2 diabetes mellitus, Metformin, Hemoglobin A1c
Brief summary
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
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).
Interventions
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.
DRUGSitagliptin
One 100 mg over-encapsulated tablet orally (by mouth) once daily for 12 weeks.
DRUGPlacebo
One matching placebo capsule orally (by mouth) once or twice daily for 12 weeks.
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 12 | Day 1 (Baseline) and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 12 | Day 1 (Baseline) and 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. |
| Percentage of Patients With Symptoms of Hypoglycemia | Up to Week 12 | The table below shows the percentage of patients who experienced symptomatic hypoglycemic events between Baseline and Week 12. |
| Change in Overnight Urine Glucose/Creatinine Ratio From Baseline to Week 12 | Day 1 (Baseline) and 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. |
| Absolute Change in Body Weight From Baseline to Week 12 | Day 1 (Baseline) and Week 12 | The table below shows the mean absolute change in body weight from Baseline to Week 12 for each treatment group. |
| Percent Change in Body Weight From Baseline to Week 12 | Day 1 (Baseline) and 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. |
Countries
Argentina, Bulgaria, Canada, Czechia, India, Malaysia, Mexico, Poland, Puerto Rico, Romania, Russia, United Kingdom, United States
Participant flow
Recruitment details
This study evaluated the efficacy and safety of canagliflozin (JNJ-28431754) in patients with type 2 diabetes mellitus with sitagliptin as a reference arm. The study was conducted between 27 March 2008 and 28 January 2009 and recruited patients from 85 study centers located in 13 countries worldwide.
Pre-assignment details
A total of 451 patients were randomly allocated to the 7 treatment arms in the study and comprised the intent-to-treat analysis set which was used for the efficacy analyses. All 451 patients received at least 1 dose of study drug and were included in the safety analysis set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Each patient received matching placebo twice daily for 12 weeks. | 65 |
| Canagliflozin 50 mg Daily Each patient received 50 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). | 64 |
| Canagliflozin 100 mg Daily Each patient received 100 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). | 64 |
| Canagliflozin 200 mg Daily Each patient received 200 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). | 65 |
| Canagliflozin 300 mg Daily Each patient received 300 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). | 64 |
| Canagliflozin 300 mg Twice Daily Each patient received 300 mg of canagliflozin (JNJ-28431754) twice daily for 12 weeks. | 64 |
| Sitagliptin 100 mg Daily Each patient received 100 mg of sitagliptin once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). | 65 |
| Total | 451 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 3 | 1 | 2 | 2 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 5 | 1 | 0 | 1 | 0 | 1 | 1 |
| Overall Study | Noncompliance with study drug regimen | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Other | 2 | 1 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 1 | 0 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 | 3 | 6 | 2 | 2 |
Baseline characteristics
| Characteristic | Canagliflozin 50 mg Daily | Canagliflozin 100 mg Daily | Canagliflozin 200 mg Daily | Canagliflozin 300 mg Daily | Placebo | Canagliflozin 300 mg Twice Daily | Sitagliptin 100 mg Daily | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 4 Participants | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 61 Participants | 63 Participants | 61 Participants | 63 Participants | 63 Participants | 62 Participants | 65 Participants | 438 Participants |
| Age Continuous | 53.3 years STANDARD_DEVIATION 8.48 | 51.7 years STANDARD_DEVIATION 7.95 | 52.9 years STANDARD_DEVIATION 9.56 | 52.3 years STANDARD_DEVIATION 6.88 | 53.3 years STANDARD_DEVIATION 7.82 | 55.2 years STANDARD_DEVIATION 7.14 | 51.7 years STANDARD_DEVIATION 8.09 | 52.9 years STANDARD_DEVIATION 8.06 |
| Region Enroll ARGENTINA | 1 participants | 3 participants | 1 participants | 2 participants | 1 participants | 0 participants | 2 participants | 10 participants |
| Region Enroll BULGARIA | 1 participants | 1 participants | 0 participants | 3 participants | 1 participants | 3 participants | 1 participants | 10 participants |
| Region Enroll CANADA | 6 participants | 9 participants | 8 participants | 8 participants | 11 participants | 4 participants | 7 participants | 53 participants |
| Region Enroll CZECH REPUBLIC | 3 participants | 2 participants | 6 participants | 0 participants | 2 participants | 2 participants | 2 participants | 17 participants |
| Region Enroll INDIA | 6 participants | 3 participants | 5 participants | 2 participants | 4 participants | 6 participants | 4 participants | 30 participants |
| Region Enroll MALAYSIA | 0 participants | 6 participants | 2 participants | 4 participants | 3 participants | 1 participants | 3 participants | 19 participants |
| Region Enroll MEXICO | 6 participants | 9 participants | 9 participants | 6 participants | 4 participants | 14 participants | 2 participants | 50 participants |
| Region Enroll POLAND | 5 participants | 4 participants | 7 participants | 6 participants | 3 participants | 5 participants | 9 participants | 39 participants |
| Region Enroll ROMANIA | 8 participants | 4 participants | 6 participants | 6 participants | 9 participants | 5 participants | 8 participants | 46 participants |
| Region Enroll RUSSIAN FEDERATION | 7 participants | 5 participants | 2 participants | 6 participants | 5 participants | 3 participants | 4 participants | 32 participants |
| Region Enroll UNITED KINGDOM | 0 participants | 2 participants | 1 participants | 3 participants | 1 participants | 1 participants | 2 participants | 10 participants |
| Region Enroll UNITED STATES | 21 participants | 16 participants | 18 participants | 18 participants | 21 participants | 20 participants | 21 participants | 135 participants |
| Sex: Female, Male Female | 30 Participants | 28 Participants | 32 Participants | 28 Participants | 34 Participants | 36 Participants | 27 Participants | 215 Participants |
| Sex: Female, Male Male | 34 Participants | 36 Participants | 33 Participants | 36 Participants | 31 Participants | 28 Participants | 38 Participants | 236 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 65 | 13 / 64 | 10 / 64 | 10 / 65 | 10 / 64 | 12 / 64 | 7 / 65 |
| serious Total, serious adverse events | 1 / 65 | 1 / 64 | 1 / 64 | 1 / 65 | 1 / 64 | 1 / 64 | 0 / 65 |
Outcome results
Primary
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.
Time frame: Day 1 (Baseline) and Week 12
Population: This analysis was conducted using the intent-to-treat analysis set, which included all patients who were randomly assigned to a treatment group. The last-observation-carried-forward method was applied when Week 12 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in HbA1c From Baseline to Week 12 | -0.22 Percent | Standard Deviation 0.702 |
| Canagliflozin 50 mg Daily | Change in HbA1c From Baseline to Week 12 | -0.79 Percent | Standard Deviation 0.749 |
| Canagliflozin 100 mg Daily | Change in HbA1c From Baseline to Week 12 | -0.76 Percent | Standard Deviation 0.992 |
| Canagliflozin 200 mg Daily | Change in HbA1c From Baseline to Week 12 | -0.70 Percent | Standard Deviation 0.72 |
| Canagliflozin 300 mg Daily | Change in HbA1c From Baseline to Week 12 | -0.92 Percent | Standard Deviation 0.695 |
| Canagliflozin 300 mg Twice Daily | Change in HbA1c From Baseline to Week 12 | -0.95 Percent | Standard Deviation 0.704 |
| Sitagliptin 100 mg Daily | Change in HbA1c From Baseline to Week 12 | -0.74 Percent | Standard Deviation 0.615 |
p-value: <0.00195% CI: [-0.747, -0.148]ANCOVA
p-value: <0.00195% CI: [-0.804, -0.207]ANCOVA
p-value: <0.00195% CI: [-0.841, -0.244]ANCOVA
p-value: <0.00195% CI: [-1.006, -0.405]ANCOVA
p-value: <0.00195% CI: [-1.029, -0.432]ANCOVA
p-value: <0.00195% CI: [-0.862, -0.265]ANCOVA
Secondary
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.
Time frame: Day 1 (Baseline) and Week 12
Population: This analysis was conducted using the intent-to-treat analysis set, which included all patients who were randomly assigned to a treatment group. The last-observation-carried-forward method was applied when Week 12 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Body Weight From Baseline to Week 12 | -0.78 kg | Standard Deviation 2.099 |
| Canagliflozin 50 mg Daily | Absolute Change in Body Weight From Baseline to Week 12 | -1.96 kg | Standard Deviation 2.334 |
| Canagliflozin 100 mg Daily | Absolute Change in Body Weight From Baseline to Week 12 | -2.25 kg | Standard Deviation 2.145 |
| Canagliflozin 200 mg Daily | Absolute Change in Body Weight From Baseline to Week 12 | -2.32 kg | Standard Deviation 2.842 |
| Canagliflozin 300 mg Daily | Absolute Change in Body Weight From Baseline to Week 12 | -2.88 kg | Standard Deviation 2.391 |
| Canagliflozin 300 mg Twice Daily | Absolute Change in Body Weight From Baseline to Week 12 | -2.87 kg | Standard Deviation 2.344 |
| Sitagliptin 100 mg Daily | Absolute Change in Body Weight From Baseline to Week 12 | -0.43 kg | Standard Deviation 2.693 |
Secondary
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.
Time frame: Day 1 (Baseline) and Week 12
Population: This analysis was conducted using the intent-to-treat analysis set, which included all patients who were randomly assigned to a treatment group. The last-observation-carried-forward method was applied when Week 12 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 12 | 0.2 mmol/L | Standard Deviation 1.58 |
| Canagliflozin 50 mg Daily | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 12 | -0.9 mmol/L | Standard Deviation 2.26 |
| Canagliflozin 100 mg Daily | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 12 | -1.4 mmol/L | Standard Deviation 1.7 |
| Canagliflozin 200 mg Daily | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 12 | -1.5 mmol/L | Standard Deviation 2.23 |
| Canagliflozin 300 mg Daily | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 12 | -1.4 mmol/L | Standard Deviation 1.87 |
| Canagliflozin 300 mg Twice Daily | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 12 | -1.3 mmol/L | Standard Deviation 1.54 |
| Sitagliptin 100 mg Daily | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 12 | -0.7 mmol/L | Standard Deviation 1.77 |
p-value: <0.00195% CI: [-1.51, -0.46]ANCOVA
p-value: <0.00195% CI: [-2.32, -1.26]ANCOVA
p-value: <0.00195% CI: [-2.25, -1.19]ANCOVA
p-value: 0.00195% CI: [-1.39, -0.34]ANCOVA
p-value: <0.00195% CI: [-1.98, -0.92]ANCOVA
p-value: <0.00195% CI: [-2.33, -1.27]ANCOVA
Secondary
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.
Time frame: Day 1 (Baseline) and Week 12
Population: This analysis was conducted using the intent-to-treat analysis set, which included all patients who were randomly assigned to a treatment group. The last-observation-carried-forward method was applied when Week 12 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Overnight Urine Glucose/Creatinine Ratio From Baseline to Week 12 | 1.9 mg/mg | Standard Deviation 12.34 |
| Canagliflozin 50 mg Daily | Change in Overnight Urine Glucose/Creatinine Ratio From Baseline to Week 12 | 35.4 mg/mg | Standard Deviation 28.98 |
| Canagliflozin 100 mg Daily | Change in Overnight Urine Glucose/Creatinine Ratio From Baseline to Week 12 | 51.5 mg/mg | Standard Deviation 28.83 |
| Canagliflozin 200 mg Daily | Change in Overnight Urine Glucose/Creatinine Ratio From Baseline to Week 12 | 50.5 mg/mg | Standard Deviation 24.38 |
| Canagliflozin 300 mg Daily | Change in Overnight Urine Glucose/Creatinine Ratio From Baseline to Week 12 | 49.4 mg/mg | Standard Deviation 38.41 |
| Canagliflozin 300 mg Twice Daily | Change in Overnight Urine Glucose/Creatinine Ratio From Baseline to Week 12 | 61.6 mg/mg | Standard Deviation 37.85 |
| Sitagliptin 100 mg Daily | Change in Overnight Urine Glucose/Creatinine Ratio From Baseline to Week 12 | -1.9 mg/mg | Standard Deviation 14.78 |
p-value: <0.00195% CI: [26.07, 46.13]ANCOVA
p-value: <0.00195% CI: [39.17, 59.34]ANCOVA
p-value: <0.00195% CI: [37.98, 58.42]ANCOVA
p-value: <0.00195% CI: [38.91, 59.01]ANCOVA
p-value: <0.00195% CI: [50.17, 70.35]ANCOVA
p-value: 0.51395% CI: [-13.33, 6.67]ANCOVA
Secondary
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.
Time frame: Up to Week 12
Population: This analysis was conducted using the intent-to-treat analysis set, which included all patients who were randomiy assigned to a treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With Symptoms of Hypoglycemia | 2 Percentage of patients |
| Canagliflozin 50 mg Daily | Percentage of Patients With Symptoms of Hypoglycemia | 0 Percentage of patients |
| Canagliflozin 100 mg Daily | Percentage of Patients With Symptoms of Hypoglycemia | 2 Percentage of patients |
| Canagliflozin 200 mg Daily | Percentage of Patients With Symptoms of Hypoglycemia | 6 Percentage of patients |
| Canagliflozin 300 mg Daily | Percentage of Patients With Symptoms of Hypoglycemia | 0 Percentage of patients |
| Canagliflozin 300 mg Twice Daily | Percentage of Patients With Symptoms of Hypoglycemia | 3 Percentage of patients |
| Sitagliptin 100 mg Daily | Percentage of Patients With Symptoms of Hypoglycemia | 5 Percentage of patients |
Secondary
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.
Time frame: Day 1 (Baseline) and Week 12
Population: This analysis was conducted using the intent-to-treat analysis set, which included all patients who were randomly assigned to a treatment group. The last-observation-carried-forward method was applied when Week 12 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change in Body Weight From Baseline to Week 12 | -1.1 Percent change | Standard Deviation 2.4 |
| Canagliflozin 50 mg Daily | Percent Change in Body Weight From Baseline to Week 12 | -2.3 Percent change | Standard Deviation 2.8 |
| Canagliflozin 100 mg Daily | Percent Change in Body Weight From Baseline to Week 12 | -2.6 Percent change | Standard Deviation 2.3 |
| Canagliflozin 200 mg Daily | Percent Change in Body Weight From Baseline to Week 12 | -2.7 Percent change | Standard Deviation 3 |
| Canagliflozin 300 mg Daily | Percent Change in Body Weight From Baseline to Week 12 | -3.4 Percent change | Standard Deviation 2.8 |
| Canagliflozin 300 mg Twice Daily | Percent Change in Body Weight From Baseline to Week 12 | -3.4 Percent change | Standard Deviation 2.6 |
| Sitagliptin 100 mg Daily | Percent Change in Body Weight From Baseline to Week 12 | -0.6 Percent change | Standard Deviation 3 |
p-value: 0.00995% CI: [-2.2, -0.3]ANCOVA
p-value: 0.00295% CI: [-2.5, -0.6]ANCOVA
p-value: <0.00195% CI: [-2.6, -0.7]ANCOVA
p-value: <0.00195% CI: [-3.3, -1.4]ANCOVA
p-value: <0.00195% CI: [-3.3, -1.4]ANCOVA
p-value: 0.37195% CI: [-0.5, 1.4]ANCOVA