Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes Mellitus, Type 2, Diabetes Mellitus, Canagliflozin (JNJ-28431754), Metformin
Brief summary
The purpose of this study is to assess the effectiveness of the co-administration of canagliflozin and metformin extended release (XR) compared with canagliflozin alone, and metformin XR alone in patients with type 2 diabetes mellitus with inadequate control despite treatment with diet and exercise. The safety and tolerability of canagliflozin will also be assessed.
Detailed description
This study will be a randomized (the study medication is assigned by chance), double-blind (neither physician nor participant knows the identity of the assigned treatment), active-controlled (one of the treatments is an established effective treatment for type 2 diabetes mellitus), parallel-group (each group of participants will be treated at the same time), 5-arm (groups), multicenter study. Approximately 1,200 participants will be randomly assigned to the 5 treatment arms in a 1:1:1:1:1 ratio for 26 weeks.
Interventions
One 100 mg capsule taken orally (by mouth) once daily either before the morning meal (for the Canagliflozin 100 mg arm) or with the evening meal (for the Canagliflozin 100 mg + Metformin XR arm).
One 300 mg capsule taken orally (by mouth) once daily either before the morning meal (for the Canagliflozin 300 mg arm) or with the evening meal (for the Canagliflozin 300 mg + Metformin XR arm).
DRUGMetformin XR
One 500 mg tablet (Day 1 up to week 1); two 500 mg tablets (Week 1 up to Week 3); three 500 mg tablets (Week 3 to Week 6); four 500 mg tablets (Week 6 to Week 9). Tablets will be administered with the evening meal.
Sponsors
Janssen Research & Development, LLC
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Must have type 2 diabetes mellitus with inadequate glycemic control on diet and exercise * Not on antihyperglycemic agent therapy (at least 12 weeks before screening) and have a screening visit fingerstick glycated hemoglobin (HbA1c) of more than or equal to 7 percent and less than or equal to 12.5 percent * Have a screening visit HbA1c of more than or equal to 7.5 percent and less than or equal to 12 percent as determined by the central laboratory * Must have a fasting plasma glucose of less than or equal to 300 mg/dL (16.7 mmol/L) prior to randomization * Must have a fasting fingerstick glucose of greater than 120 mg/dL (6.7 mmol/L) performed at home or at the study center prior to randomization
Exclusion criteria
* History of diabetic ketoacidosis, type 1 diabetes mellitus (T1DM), pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy * Fasting C-peptide less than 0.70 ng/mL (0.23 nmol/L) in participants for whom the investigator cannot reasonably exclude T1DM based upon clinical evaluation * Repeated (2 or more over a 1 week period) fasting self-monitored blood glucose measurements more than 300 mg/dL (16.7 mmol/L) prior to randomization, despite reinforcement of diet and exercise counseling * History of hereditary glucose-galactose malabsorption or primary renal glucosuria * Has history of, or currently active, illness considered to be clinically significant by the Investigator or any other illness that the Investigator considers should exclude the patient from the study or that could interfere with the interpretation of the study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycated Hemoglobin (HbA1c) From Baseline at Week 26 | Day 1 (Baseline) and Week 26 | The change in the value of glycated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) from baseline at Week 26 was compared between the different treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Glycated Hemoglobin (HbAIc) Less Than 7 Percent at Week 26 | Week 26 | The percentage of participants achieved HbAIc less than 7 percent at Week 26 was compared between the different treatment groups. |
| Change in Systolic Blood Pressure From Baseline at Week 26 | Day 1 (Baseline) and Week 26 | The change in systolic blood pressure from baseline at Week 26 was compared between the different treatment groups. |
| Percent Change in Body Weight From Baseline to Week 26 | Day 1 (Baseline) and Week 26 | The percentage change in body weight from baseline to Week 26 was compared between the different treatment groups. |
| Percent Change in Triglycerides From Baseline to Week 26 | Day 1 (Baseline) and Week 26 | The percentage change in triglycerides from baseline to Week 26 was compared between the different treatment groups. |
| Number of Participants With Treatment Emergent Adverse Events (AEs) | Up to 30 weeks of last study drug administration | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between administration of study drug and up to 30 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. |
| Percent Change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | Day 1 (Baseline) and Week 26 | The percentage change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) from baseline to Week 26 was compared between the different treatment groups. |
Countries
Argentina, Brazil, Czechia, Hungary, Mexico, Puerto Rico, Romania, Russia, Slovakia, South Africa, South Korea, Ukraine, United States
Participant flow
Recruitment details
The study was conducted between 16 May 2013 and 01 December 2014 and recruited participants from 158 study centers in 12 countries worldwide.
Pre-assignment details
A total of 1,186 participants were randomly allocated to the 5 treatment arms. All participants received at least 1 dose of study drug and were included in the modified intent-to-treat (mITT) analysis set.
Participants by arm
| Arm | Count |
|---|---|
| Metformin XR Participants received metformin extended release (XR) tablets (in doses titrated over 9 weeks) once daily with the evening meal, plus one placebo capsule before the morning meal and one placebo capsule with the evening meal (to match the canagliflozin capsules administered in other treatment arms) for 26 weeks. | 237 |
| Canagliflozin 100 Milligram (mg) Participants received one 100 milligram (mg) canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks. | 237 |
| Canagliflozin 300 mg Participants received one 300 mg canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks. | 238 |
| Canagliflozin 100 mg + Metformin XR Participants received one 100 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks. | 237 |
| Canagliflozin 300 mg + Metformin XR Participants received one 300 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks. | 237 |
| Total | 1,186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 | 7 | 4 | 8 |
| Overall Study | Death | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 5 | 2 | 4 | 2 | 3 |
| Overall Study | Other | 14 | 15 | 7 | 4 | 9 |
| Overall Study | Physician Decision | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Pregnancy | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 4 | 4 | 2 | 5 |
Baseline characteristics
| Characteristic | Metformin XR | Total | Canagliflozin 300 mg + Metformin XR | Canagliflozin 100 mg + Metformin XR | Canagliflozin 300 mg | Canagliflozin 100 Milligram (mg) |
|---|---|---|---|---|---|---|
| Age, Continuous | 55.2 years STANDARD_DEVIATION 9.75 | 54.9 years STANDARD_DEVIATION 9.91 | 55.4 years STANDARD_DEVIATION 9.84 | 54.2 years STANDARD_DEVIATION 9.58 | 55.8 years STANDARD_DEVIATION 9.56 | 54.0 years STANDARD_DEVIATION 10.7 |
| Region of Enrollment Argentina | 12 participants | 89 participants | 20 participants | 17 participants | 21 participants | 19 participants |
| Region of Enrollment Brazil | 1 participants | 4 participants | 0 participants | 0 participants | 1 participants | 2 participants |
| Region of Enrollment Czech Republic | 8 participants | 34 participants | 8 participants | 6 participants | 6 participants | 6 participants |
| Region of Enrollment Hungary | 2 participants | 28 participants | 4 participants | 9 participants | 8 participants | 5 participants |
| Region of Enrollment Mexico | 33 participants | 159 participants | 38 participants | 38 participants | 19 participants | 31 participants |
| Region of Enrollment Romania | 24 participants | 102 participants | 14 participants | 27 participants | 21 participants | 16 participants |
| Region of Enrollment Russian Federation | 38 participants | 202 participants | 37 participants | 44 participants | 45 participants | 38 participants |
| Region of Enrollment Slovakia | 17 participants | 69 participants | 9 participants | 9 participants | 22 participants | 12 participants |
| Region of Enrollment South Africa | 5 participants | 22 participants | 3 participants | 5 participants | 4 participants | 5 participants |
| Region of Enrollment South Korea | 4 participants | 12 participants | 3 participants | 1 participants | 2 participants | 2 participants |
| Region of Enrollment Ukraine | 50 participants | 242 participants | 54 participants | 40 participants | 42 participants | 56 participants |
| Region of Enrollment United States | 43 participants | 223 participants | 47 participants | 41 participants | 47 participants | 45 participants |
| Sex: Female, Male Female | 121 Participants | 617 Participants | 122 Participants | 129 Participants | 113 Participants | 132 Participants |
| Sex: Female, Male Male | 116 Participants | 569 Participants | 115 Participants | 108 Participants | 125 Participants | 105 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 37 / 237 | 38 / 237 | 38 / 238 | 42 / 237 | 43 / 237 |
| serious Total, serious adverse events | 7 / 237 | 4 / 237 | 7 / 238 | 7 / 237 | 4 / 237 |
Outcome results
Primary
Change in Glycated Hemoglobin (HbA1c) From Baseline at Week 26
The change in the value of glycated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) from baseline at Week 26 was compared between the different treatment groups.
Time frame: Day 1 (Baseline) and Week 26
Population: This analysis was conducted using the modified intent-to-treat analysis set, which included all participants who were randomly assigned to a treatment group and received at least 1 dose of study drug. Here N (Number of Participants Analyzed) signifies number of Participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Metformin XR | Change in Glycated Hemoglobin (HbA1c) From Baseline at Week 26 | -1.30 percentage of hemoglobin | Standard Error 0.071 |
| Canagliflozin 100 Milligram (mg) | Change in Glycated Hemoglobin (HbA1c) From Baseline at Week 26 | -1.37 percentage of hemoglobin | Standard Error 0.071 |
| Canagliflozin 300 mg | Change in Glycated Hemoglobin (HbA1c) From Baseline at Week 26 | -1.42 percentage of hemoglobin | Standard Error 0.07 |
| Canagliflozin 100 mg + Metformin XR | Change in Glycated Hemoglobin (HbA1c) From Baseline at Week 26 | -1.77 percentage of hemoglobin | Standard Error 0.069 |
| Canagliflozin 300 mg + Metformin XR | Change in Glycated Hemoglobin (HbA1c) From Baseline at Week 26 | -1.78 percentage of hemoglobin | Standard Error 0.07 |
p-value: 0.00195% CI: [-0.657, -0.269]Mixed Model for Repeated Measures (MMRM)
p-value: 0.00195% CI: [-0.67, -0.28]Mixed Model for Repeated Measures (MMRM)
p-value: 0.00195% CI: [-0.594, -0.207]Mixed Model for Repeated Measures (MMRM)
p-value: 0.00195% CI: [-0.557, -0.169]Mixed Model for Repeated Measures (MMRM)
p-value: 0.00195% CI: [-0.258, 0.133]Mixed Model for Repeated Measures (MMRM)
p-value: 0.00195% CI: [-0.307, 0.082]Mixed Model for Repeated Measures (MMRM)
Secondary
Change in Systolic Blood Pressure From Baseline at Week 26
The change in systolic blood pressure from baseline at Week 26 was compared between the different treatment groups.
Time frame: Day 1 (Baseline) and Week 26
Population: This analysis was conducted using the modified intent-to-treat analysis set, which included all participants who were randomly assigned to a treatment group and received at least 1 dose of study drug. Here N (Number of Participants Analyzed) signifies number of Participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Metformin XR | Change in Systolic Blood Pressure From Baseline at Week 26 | -0.33 millimeter of mercury (mm Hg) | Standard Error 0.633 |
| Canagliflozin 100 Milligram (mg) | Change in Systolic Blood Pressure From Baseline at Week 26 | -2.24 millimeter of mercury (mm Hg) | Standard Error 0.627 |
| Canagliflozin 300 mg | Change in Systolic Blood Pressure From Baseline at Week 26 | -2.36 millimeter of mercury (mm Hg) | Standard Error 0.622 |
| Canagliflozin 100 mg + Metformin XR | Change in Systolic Blood Pressure From Baseline at Week 26 | -2.24 millimeter of mercury (mm Hg) | Standard Error 0.613 |
| Canagliflozin 300 mg + Metformin XR | Change in Systolic Blood Pressure From Baseline at Week 26 | -1.65 millimeter of mercury (mm Hg) | Standard Error 0.624 |
p-value: 0.0695% CI: [-3.641, -0.182]Mixed Model for Repeated Measures (MMRM)
p-value: 0.14795% CI: [-3.058, 0.431]Mixed Model for Repeated Measures (MMRM)
Secondary
Number of Participants With Treatment Emergent Adverse Events (AEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between administration of study drug and up to 30 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state.
Time frame: Up to 30 weeks of last study drug administration
Population: Safety Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin XR | Number of Participants With Treatment Emergent Adverse Events (AEs) | 89 participants |
| Canagliflozin 100 Milligram (mg) | Number of Participants With Treatment Emergent Adverse Events (AEs) | 88 participants |
| Canagliflozin 300 mg | Number of Participants With Treatment Emergent Adverse Events (AEs) | 95 participants |
| Canagliflozin 100 mg + Metformin XR | Number of Participants With Treatment Emergent Adverse Events (AEs) | 99 participants |
| Canagliflozin 300 mg + Metformin XR | Number of Participants With Treatment Emergent Adverse Events (AEs) | 105 participants |
Secondary
Percentage of Participants With Glycated Hemoglobin (HbAIc) Less Than 7 Percent at Week 26
The percentage of participants achieved HbAIc less than 7 percent at Week 26 was compared between the different treatment groups.
Time frame: Week 26
Population: This analysis was conducted using the modified intent-to-treat analysis set, which included all participants who were randomly assigned to a treatment group and received at least 1 dose of study drug. Here N (Number of Participants Analyzed) signifies number of Participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin XR | Percentage of Participants With Glycated Hemoglobin (HbAIc) Less Than 7 Percent at Week 26 | 43.0 percentage of participants |
| Canagliflozin 100 Milligram (mg) | Percentage of Participants With Glycated Hemoglobin (HbAIc) Less Than 7 Percent at Week 26 | 38.8 percentage of participants |
| Canagliflozin 300 mg | Percentage of Participants With Glycated Hemoglobin (HbAIc) Less Than 7 Percent at Week 26 | 42.8 percentage of participants |
| Canagliflozin 100 mg + Metformin XR | Percentage of Participants With Glycated Hemoglobin (HbAIc) Less Than 7 Percent at Week 26 | 49.6 percentage of participants |
| Canagliflozin 300 mg + Metformin XR | Percentage of Participants With Glycated Hemoglobin (HbAIc) Less Than 7 Percent at Week 26 | 56.8 percentage of participants |
p-value: 0.02795% CI: [1.06, 2.37]Generalized Linear Mixed Model
p-value: 0.01695% CI: [1.46, 3.33]Generalized Linear Mixed Model
Secondary
Percent Change in Body Weight From Baseline to Week 26
The percentage change in body weight from baseline to Week 26 was compared between the different treatment groups.
Time frame: Day 1 (Baseline) and Week 26
Population: This analysis was conducted using the modified intent-to-treat analysis set, which included all participants who were randomly assigned to a treatment group and received at least 1 dose of study drug. Here N (Number of Participants Analyzed) signifies number of Participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Metformin XR | Percent Change in Body Weight From Baseline to Week 26 | -2.1 percent change | Standard Error 0.3 |
| Canagliflozin 100 Milligram (mg) | Percent Change in Body Weight From Baseline to Week 26 | -3.0 percent change | Standard Error 0.3 |
| Canagliflozin 300 mg | Percent Change in Body Weight From Baseline to Week 26 | -3.9 percent change | Standard Error 0.3 |
| Canagliflozin 100 mg + Metformin XR | Percent Change in Body Weight From Baseline to Week 26 | -3.5 percent change | Standard Error 0.3 |
| Canagliflozin 300 mg + Metformin XR | Percent Change in Body Weight From Baseline to Week 26 | -4.2 percent change | Standard Error 0.3 |
p-value: 0.01695% CI: [-1.6, -0.2]Mixed Model for Repeated Measures (MMRM)
p-value: 0.00295% CI: [-2.6, -1.1]Mixed Model for Repeated Measures (MMRM)
p-value: 0.00195% CI: [-2.1, -0.6]Mixed Model for Repeated Measures (MMRM)
p-value: 0.00195% CI: [-2.9, -1.4]Mixed Model for Repeated Measures (MMRM)
Secondary
Percent Change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26
The percentage change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) from baseline to Week 26 was compared between the different treatment groups.
Time frame: Day 1 (Baseline) and Week 26
Population: Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Here N (Number of Participants Analyzed) signifies number of Participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Metformin XR | Percent Change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 10.2 percent change | Standard Error 1.5 |
| Canagliflozin 100 Milligram (mg) | Percent Change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 17.6 percent change | Standard Error 1.5 |
| Canagliflozin 300 mg | Percent Change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 16.6 percent change | Standard Error 1.5 |
| Canagliflozin 100 mg + Metformin XR | Percent Change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 15.5 percent change | Standard Error 1.5 |
| Canagliflozin 300 mg + Metformin XR | Percent Change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 14.5 percent change | Standard Error 1.5 |
p-value: 0.14795% CI: [1.2, 9.5]ANCOVA
p-value: 0.14795% CI: [0.2, 8.5]ANCOVA
Secondary
Percent Change in Triglycerides From Baseline to Week 26
The percentage change in triglycerides from baseline to Week 26 was compared between the different treatment groups.
Time frame: Day 1 (Baseline) and Week 26
Population: Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Here N (Number of Participants Analyzed) signifies number of Participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin XR | Percent Change in Triglycerides From Baseline to Week 26 | 13.6 percent change | Standard Deviation 51.8 |
| Canagliflozin 100 Milligram (mg) | Percent Change in Triglycerides From Baseline to Week 26 | 1.7 percent change | Standard Deviation 50.5 |
| Canagliflozin 300 mg | Percent Change in Triglycerides From Baseline to Week 26 | 2.8 percent change | Standard Deviation 60.3 |
| Canagliflozin 100 mg + Metformin XR | Percent Change in Triglycerides From Baseline to Week 26 | 13.0 percent change | Standard Deviation 81.9 |
| Canagliflozin 300 mg + Metformin XR | Percent Change in Triglycerides From Baseline to Week 26 | 21.2 percent change | Standard Deviation 71.1 |
p-value: 0.60895% CI: [-11.1, 3.4]Wilcoxon (Mann-Whitney)
p-value: 0.80695% CI: [-7.3, 10]Wilcoxon (Mann-Whitney)