The CANTATA-MSU Trial (CANagliflozin Treatment And Trial Analysis - Metformin and SUlphonylurea)

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01106625
• Collaborator: (none)
• Enrollment: 469
• Locations: 76
• Arms: 3
• Duration (Months): 23
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of 2 different doses of canagliflozin compared with placebo in patients with type 2 diabetes mellitus who are receiving treatment with metformin and sulphonylurea and have inadequate glycemic (blood sugar) control.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Canagliflozin; Drug: Placebo; Drug: Metformin; Drug: Sulphonylruea	Phase 3

Detailed Description

Canagliflozin is a drug that is being tested to see if it may be useful in treating patients diagnosed with type 2 diabetes mellitus (T2DM). This is a randomized (study drug assigned by chance), double-blind (neither the patient or the study doctor will know the name of the assigned treatment), placebo-controlled, parallel-group, 3-arm (3 treatment groups) multicenter study to determine the efficacy, safety, and tolerability of canagliflozin (100 mg and 300 mg) compared to placebo (a capsule that looks like all the other treatments but has no real medicine) in patients with T2DM who are not achieving an adequate response from current antihyperglycemic therapy with metformin and sulphonylurea to control their diabetes. Approximately 450 patients with T2DM who are receiving treatment with metformin and sulphonylurea and have inadequate glycemic (blood sugar) control will receive once daily treatment with canagliflozin (100 mg or 300 mg) or placebo capsules for 52 weeks (includes 26 weeks of double-blind treatment followed by a 26-week extension period). In addition, all patients will take protocol-specified stable doses of metformin and sulphonylurea for the duration of the study. Patients will participate in the study for approximately 59 to 72 weeks. During the study, if a patient's fasting blood sugar remains high despite treatment with study drug, the patient will receive treatment with insulin (rescue therapy) consistent with local prescribing information. During treatment, patients will be monitored for safety by review of adverse events, results from laboratory tests, 12-lead electrocardiograms (ECGs), vital signs measurements, body weight, physical examinations, and self-monitored blood glucose (SMGB) measurements. The primary outcome measure in the study is to assess the effect of canagliflozin relative to placebo on hemoglobin A1c (HbA1c) after 26 weeks of treatment. Study drug will be taken orally (by mouth) once daily before the first meal each day unless otherwise specified. All patients will take single-blind placebo capsules for 2 weeks before randomization. After randomization, patients will take double-blind canagliflozin (100 mg or 300 mg) or matching placebo for 52 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 469 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, 3-Arm, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin in the Treatment of Subjects With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin and Sulphonylurea Therapy
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Canagliflozin 100 mg Each patient will receive 100 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Drug: Canagliflozin; One 100 mg or 300 mg over-encapsulated tablet orally (by mouth) once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.; Drug: Metformin; The patient's stable dose of background metformin therapy should be continued throughout the study.; Drug: Sulphonylruea; The patient's stable dose of background sulphonylurea therapy should be continued throughout the study.
Experimental: Canagliflozin 300 mg Each patient will receive 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Drug: Canagliflozin; One 100 mg or 300 mg over-encapsulated tablet orally (by mouth) once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.; Drug: Metformin; The patient's stable dose of background metformin therapy should be continued throughout the study.; Drug: Sulphonylruea; The patient's stable dose of background sulphonylurea therapy should be continued throughout the study.
Placebo Comparator: Placebo Each patient will receive matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Drug: Placebo; One matching placebo capsule orally once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.; Drug: Metformin; The patient's stable dose of background metformin therapy should be continued throughout the study.; Drug: Sulphonylruea; The patient's stable dose of background sulphonylurea therapy should be continued throughout the study.

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c From Baseline to Week 26 [Day 1 (Baseline) and Week 26]

   The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.

Secondary Outcome Measures

1. Percentage of Patients With HbA1c <7% at Week 26 [Week 26]

   The table below shows the percentage of patients with HbA1c<7% at Week 26 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage.

2. Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 [Day 1 (Baseline) and Week 26]

   The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.

3. Percent Change in Body Weight From Baseline to Week 26 [Day 1 (Baseline) and Week 26]

   The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.

4. Change in Systolic Blood Pressure (SBP) From Baseline to Week 26 [Day 1 (Baseline) and Week 26]

   The table below shows the least-squares (LS) mean change in SBP from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.

5. Percent Change in Triglycerides From Baseline to Week 26 [Day 1 (Baseline) and Week 26]

   The table below shows the least-squares (LS) mean percent change in triglycerides from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.

6. Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 [Day 1 (Baseline) and Week 26]

   The table below shows the least-squares (LS) mean percent change in HDL-C from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• All patients must have a diagnosis of T2DM and be currently treated with metformin and sulphonylurea

• Patients in the study must have a HbA1c between >=7 and <=10.5%

• Patients must have a fasting plasma glucose (FPG) <270 mg/dL (15 mmol/L)

Exclusion Criteria:

• History of diabetic ketoacidosis, type 1 diabetes mellitus (T1DM), pancreas or beta cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy, or a severe hypoglycemic episode within 6 months before screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Huntsville	Alabama	United States
2		Little Rock	Alaska	United States
3		Phoenix	Arizona	United States
4		Chino	California	United States
5		Fair Oaks	California	United States
6		Roseville	California	United States
7		Wes Hills	California	United States
8		Waterbury	Connecticut	United States
9		Jacksonville	Florida	United States
10		New Port Richey	Florida	United States
11		Ocala	Florida	United States
12		St Petersburg	Florida	United States
13		West Palm Beach	Florida	United States
14		Augusta	Georgia	United States
15		Roswell	Georgia	United States
16		Chicago	Illinois	United States
17		Lexington	Kentucky	United States
18		New Orleans	Louisiana	United States
19		Reisterstown	Maryland	United States
20		Olive Branch	Mississippi	United States
21		Saint Louis	Missouri	United States
22		Westfield	New York	United States
23		Greenville	North Carolina	United States
24		Cincinnati	Ohio	United States
25		Tulsa	Oklahoma	United States
26		Medford	Oregon	United States
27		Altoona	Pennsylvania	United States
28		Harleysville	Pennsylvania	United States
29		Levittown	Pennsylvania	United States
30		Sellersville	Pennsylvania	United States
31		Greer	South Carolina	United States
32		Bryan	Texas	United States
33		Dallas	Texas	United States
34		Desoto	Texas	United States
35		Salt Lake City	Utah	United States
36		South Burlington	Vermont	United States
37		Wenatchee	Washington	United States
38		Freemantle		Australia
39		Heidelberg Heights		Australia
40		Meadowbrook		Australia
41		Nedlands		Australia
42		Wollongong		Australia
43		Aalst		Belgium
44		Bonheiden		Belgium
45		Edegem		Belgium
46		Leuven		Belgium
47		Corbeil Essonnes		France
48		La Rochelle		France
49		Le Creusot		France
50		Poitiers		France
51		Venissieux		France
52		Guatemala		Guatemala
53		Balatonfured		Hungary
54		Budapest		Hungary
55		Győr		Hungary
56		Zalaegerszeg		Hungary
57		Haifa		Israel
58		Holon		Israel
59		Jerusalem		Israel
60		Tel Aviv		Israel
61		Guadalajara		Mexico
62		Monterrey		Mexico
63		Carolina		Puerto Rico
64		Trujillo Alto		Puerto Rico
65		Arkhangelsk		Russian Federation
66		Saint Petersburg		Russian Federation
67		Samara		Russian Federation
68		Alicante		Spain
69		Almeria		Spain
70		Malaga		Spain
71		Sevilla		Spain
72		Valencia		Spain
73		Belfast		United Kingdom
74		Bolton		United Kingdom
75		Liverpool		United Kingdom
76		Manchester		United Kingdom

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC C. Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01106625
• Other Study ID Numbers: CR017005; 28431754DIA3002
• First Posted: Apr 20, 2010
• Last Update Posted: Jun 20, 2013
• Last Verified: Jun 1, 2013

• Keywords provided by Janssen Research & Development, LLC: Canagliflozin; Placebo; Metformin; Sulphonylurea; Hemoglobin A1c; Type 2 diabetes mellitus
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Canagliflozin

Study Results

Participant Flow

Recruitment Details	This study evaluated the efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus with inadequate control despite treatment with metformin and sulphonylurea therapy. The study was conducted between 07 April 2010 and 17 April 2012 and recruited patients from 85 study centers in 11 countries worldwide.
Pre-assignment Detail	A total of 469 patients were randomly allocated to the 3 treatment arms in the study. All 469 patients received at least 1 dose of study drug and were included in the modified intent-to-treat analysis set (used for the week 26 efficacy analyses). All 469 patients were included in the week 26 and week 52 safety analysis sets.

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.
Period Title: Core Period: Baseline to Week 26
STARTED	156	157	156
COMPLETED	123	129	129
NOT COMPLETED	33	28	27
Period Title: Core Period: Baseline to Week 26
STARTED	119	127	128
COMPLETED	90	109	111
NOT COMPLETED	29	18	17

Baseline Characteristics

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg	Total
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Total of all reporting groups
Overall Participants	156	157	156	469
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	130 83.3%	121 77.1%	134 85.9%	385 82.1%
>=65 years	26 16.7%	36 22.9%	22 14.1%	84 17.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.7 (8.36)	57.3 (10.47)	56 (8.95)	56.7 (9.3)
Sex: Female, Male (Count of Participants)
Female	80 51.3%	81 51.6%	69 44.2%	230 49%
Male	76 48.7%	76 48.4%	87 55.8%	239 51%
Region of Enrollment (participants) [Number]
AUSTRALIA	3 1.9%	6 3.8%	4 2.6%	13 2.8%
BELGIUM	3 1.9%	1 0.6%	6 3.8%	10 2.1%
FRANCE	4 2.6%	7 4.5%	9 5.8%	20 4.3%
GUATEMALA	15 9.6%	12 7.6%	16 10.3%	43 9.2%
HUNGARY	11 7.1%	14 8.9%	11 7.1%	36 7.7%
ISRAEL	1 0.6%	6 3.8%	8 5.1%	15 3.2%
MEXICO	11 7.1%	11 7%	11 7.1%	33 7%
RUSSIAN FEDERATION	14 9%	13 8.3%	8 5.1%	35 7.5%
SPAIN	5 3.2%	7 4.5%	8 5.1%	20 4.3%
UNITED KINGDOM	8 5.1%	6 3.8%	5 3.2%	19 4.1%
UNITED STATES	81 51.9%	74 47.1%	70 44.9%	225 48%

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c From Baseline to Week 26
Description	The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
Time Frame	Day 1 (Baseline) and Week 26

Outcome Measure Data

Analysis Population Description

Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 26 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 100 mg of canagliflozin once daily for for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.
Measure Participants	150	155	152
Least Squares Mean (Standard Error) [Percent]	-0.13 (0.075)	-0.85 (0.075)	-1.06 (0.076)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-0.71
	Confidence Interval	(2-Sided) 95%; -0.904 to -0.524
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.097
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-0.92
	Confidence Interval	(2-Sided) 95%; -1.114 to -0.732
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.097
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Patients With HbA1c <7% at Week 26
Description	The table below shows the percentage of patients with HbA1c<7% at Week 26 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 26 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 100 mg of canagliflozin once daily for for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.
Measure Participants	150	155	152
Number [Percentage of patients]	18	43.2	56.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.42
	Confidence Interval	(2-Sided) 95%; 2.48 to 7.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	8.80
	Confidence Interval	(2-Sided) 95%; 4.86 to 15.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26
Description	The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
Time Frame	Day 1 (Baseline) and Week 26

Outcome Measure Data

Analysis Population Description

Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 26 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 100 mg of canagliflozin once daily for for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.
Measure Participants	150	155	152
Least Squares Mean (Standard Error) [mg/dL]	4.11 (3.629)	-18.2 (3.629)	-30.5 (3.650)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-22.3
	Confidence Interval	(2-Sided) 95%; -31.53 to -13.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.627
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-34.6
	Confidence Interval	(2-Sided) 95%; -43.86 to -25.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.692
	Estimation Comments

4. Secondary Outcome

Title	Percent Change in Body Weight From Baseline to Week 26
Description	The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.
Time Frame	Day 1 (Baseline) and Week 26

Outcome Measure Data

Analysis Population Description

Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 26 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 100 mg of canagliflozin once daily for for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.
Measure Participants	150	156	154
Least Squares Mean (Standard Error) [Percent change]	-0.7 (0.3)	-2.1 (0.3)	-2.6 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -2.1 to -0.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 95%; -2.7 to -1.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4
	Estimation Comments

5. Secondary Outcome

Title	Change in Systolic Blood Pressure (SBP) From Baseline to Week 26
Description	The table below shows the least-squares (LS) mean change in SBP from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
Time Frame	Day 1 (Baseline) and Week 26

Outcome Measure Data

Analysis Population Description

Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 26 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 100 mg of canagliflozin once daily for for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.
Measure Participants	150	156	154
Least Squares Mean (Standard Error) [mmHg]	-2.65 (0.982)	-4.89 (0.976)	-4.27 (0.980)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.077
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-2.24
	Confidence Interval	(2-Sided) 95%; -4.719 to 0.241
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.262
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.201
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-1.62
	Confidence Interval	(2-Sided) 95%; -4.111 to 0.866
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.266
	Estimation Comments

6. Secondary Outcome

Title	Percent Change in Triglycerides From Baseline to Week 26
Description	The table below shows the least-squares (LS) mean percent change in triglycerides from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.
Time Frame	Day 1 (Baseline) and Week 26

Outcome Measure Data

Analysis Population Description

Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 26 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 100 mg of canagliflozin once daily for for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.
Measure Participants	134	145	142
Least Squares Mean (Standard Error) [Percent change]	11.6 (4.2)	5.4 (4.2)	8.5 (4.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.256
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-6.2
	Confidence Interval	(2-Sided) 95%; -16.9 to 4.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.4
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.571
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95%; -13.8 to 7.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.5
	Estimation Comments

7. Secondary Outcome

Title	Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26
Description	The table below shows the least-squares (LS) mean percent change in HDL-C from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.
Time Frame	Day 1 (Baseline) and Week 26

Outcome Measure Data

Analysis Population Description

Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 26 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 100 mg of canagliflozin once daily for for 52 weeks with protocol-specified doses of metformin and sulphonylurea.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea.
Measure Participants	135	145	141
Least Squares Mean (Standard Error) [Percent change]	3.2 (1.3)	5.7 (1.3)	6.5 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.153
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; -0.9 to 5.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.7
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; -0.1 to 6.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.8
	Estimation Comments

Adverse Events

Time Frame	Adverse events were reported for the duration of the study; each patient participated in the study for approximately 52 weeks.
Adverse Event Reporting Description	The total number of adverse events listed in the "Other (non-Serious) Adverse Events" table are based upon a cut-off of greater than or equal to 5 percent of patients experiencing the adverse event in any treatment arm.
Arm/Group Title	Placebo: Baseline to Week 26		Canagliflozin 100 mg: Baseline to Week 26		Canagliflozin 300 mg: Baseline to Week 26		Placebo: Baseline to Week 52		Canagliflozin 100 mg: Baseline to Week 52		Canagliflozin 300 mg: Baseline to Week 52
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea. Data are presented for Baseline to Week 26.		Each patient received 100 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea. Data are presented for Baseline to Week 26.		Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea. Data are presented for Baseline to Week 26.		Each patient received matching placebo once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea. Data are presented for Baseline to Week 52.		Each patient received 100 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea. Data are presented for Baseline to Week 52.		Each patient received 300 mg of canagliflozin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea. Data are presented for Baseline to Week 52.
All Cause Mortality
	Placebo: Baseline to Week 26		Canagliflozin 100 mg: Baseline to Week 26		Canagliflozin 300 mg: Baseline to Week 26		Placebo: Baseline to Week 52		Canagliflozin 100 mg: Baseline to Week 52		Canagliflozin 300 mg: Baseline to Week 52
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo: Baseline to Week 26		Canagliflozin 100 mg: Baseline to Week 26		Canagliflozin 300 mg: Baseline to Week 26		Placebo: Baseline to Week 52		Canagliflozin 100 mg: Baseline to Week 52		Canagliflozin 300 mg: Baseline to Week 52
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/156 (5.8%)		5/157 (3.2%)		6/156 (3.8%)		13/156 (8.3%)		7/157 (4.5%)		8/156 (5.1%)
Cardiac disorders
Angina pectoris	0/156 (0%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Atrial fibrillation	0/156 (0%)		1/157 (0.6%)		0/156 (0%)		0/156 (0%)		1/157 (0.6%)		0/156 (0%)
Coronary artery stenosis	1/156 (0.6%)		1/157 (0.6%)		0/156 (0%)		1/156 (0.6%)		1/157 (0.6%)		0/156 (0%)
Myocardial infarction	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Gastrointestinal disorders
Abdominal pain	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Mechanical ileus	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
General disorders
Chest pain	0/156 (0%)		0/157 (0%)		0/156 (0%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Ulcer haemorrhage	0/156 (0%)		0/157 (0%)		1/156 (0.6%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Hepatobiliary disorders
Biliary dyskinesia	0/156 (0%)		0/157 (0%)		1/156 (0.6%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Cholecystitis	0/156 (0%)		0/157 (0%)		1/156 (0.6%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Cholecystitis chronic	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Infections and infestations
Diverticulitis	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Gangrene	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Lobar pneumonia	1/156 (0.6%)		0/157 (0%)		1/156 (0.6%)		1/156 (0.6%)		0/157 (0%)		1/156 (0.6%)
Pneumonia	0/156 (0%)		1/157 (0.6%)		0/156 (0%)		0/156 (0%)		1/157 (0.6%)		0/156 (0%)
Scrotal gangrene	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Urinary tract infection	0/156 (0%)		0/157 (0%)		1/156 (0.6%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Urosepsis	0/156 (0%)		1/157 (0.6%)		0/156 (0%)		0/156 (0%)		1/157 (0.6%)		0/156 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/156 (0%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Road traffic accident	0/156 (0%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Wound complication	0/156 (0%)		0/157 (0%)		1/156 (0.6%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/156 (0%)		0/157 (0%)		0/156 (0%)		0/156 (0%)		1/157 (0.6%)		0/156 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/156 (0%)		1/157 (0.6%)		0/156 (0%)		0/156 (0%)		1/157 (0.6%)		0/156 (0%)
Musculoskeletal chest pain	0/156 (0%)		0/157 (0%)		1/156 (0.6%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Spinal osteoarthritis	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Back pain	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	1/156 (0.6%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Nervous system disorders
Cerebrovascular accident	0/156 (0%)		1/157 (0.6%)		0/156 (0%)		0/156 (0%)		1/157 (0.6%)		0/156 (0%)
Renal and urinary disorders
Nephrolithiasis	0/156 (0%)		0/157 (0%)		0/156 (0%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Urinary incontinence	0/156 (0%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Calculus ureteric	0/156 (0%)		1/157 (0.6%)		0/156 (0%)		0/156 (0%)		1/157 (0.6%)		0/156 (0%)
Hydronephrosis	0/156 (0%)		1/157 (0.6%)		0/156 (0%)		0/156 (0%)		1/157 (0.6%)		0/156 (0%)
Reproductive system and breast disorders
Uterine enlargement	0/156 (0%)		0/157 (0%)		0/156 (0%)		1/156 (0.6%)		0/157 (0%)		0/156 (0%)
Uterine prolapse	0/156 (0%)		0/157 (0%)		0/156 (0%)		0/156 (0%)		1/157 (0.6%)		0/156 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	0/156 (0%)		0/157 (0%)		1/156 (0.6%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Vascular disorders
Deep vein thrombosis	0/156 (0%)		0/157 (0%)		1/156 (0.6%)		0/156 (0%)		0/157 (0%)		1/156 (0.6%)
Other (Not Including Serious) Adverse Events
	Placebo: Baseline to Week 26		Canagliflozin 100 mg: Baseline to Week 26		Canagliflozin 300 mg: Baseline to Week 26		Placebo: Baseline to Week 52		Canagliflozin 100 mg: Baseline to Week 52		Canagliflozin 300 mg: Baseline to Week 52
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/156 (19.9%)		42/157 (26.8%)		38/156 (24.4%)		52/156 (33.3%)		63/157 (40.1%)		54/156 (34.6%)
Gastrointestinal disorders
Diarrhoea	5/156 (3.2%)		5/157 (3.2%)		10/156 (6.4%)		5/156 (3.2%)		8/157 (5.1%)		11/156 (7.1%)
Infections and infestations
Influenza	0/156 (0%)		0/157 (0%)		0/156 (0%)		8/156 (5.1%)		4/157 (2.5%)		8/156 (5.1%)
Sinusitis	0/156 (0%)		0/157 (0%)		0/156 (0%)		3/156 (1.9%)		8/157 (5.1%)		3/156 (1.9%)
Nasopharyngitis	4/156 (2.6%)		6/157 (3.8%)		8/156 (5.1%)		10/156 (6.4%)		9/157 (5.7%)		9/156 (5.8%)
Upper respiratory tract infection	10/156 (6.4%)		17/157 (10.8%)		6/156 (3.8%)		13/156 (8.3%)		21/157 (13.4%)		9/156 (5.8%)
Urinary tract infection	8/156 (5.1%)		9/157 (5.7%)		7/156 (4.5%)		12/156 (7.7%)		12/157 (7.6%)		9/156 (5.8%)
Vulvovaginal mycotic infection	2/156 (1.3%)		8/157 (5.1%)		8/156 (5.1%)		2/156 (1.3%)		9/157 (5.7%)		8/156 (5.1%)
Metabolism and nutrition disorders
Hypoglycaemia	6/156 (3.8%)		11/157 (7%)		9/156 (5.8%)		9/156 (5.8%)		13/157 (8.3%)		11/156 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/156 (0%)		0/157 (0%)		0/156 (0%)		8/156 (5.1%)		8/157 (5.1%)		8/156 (5.1%)
Nervous system disorders
Headache	0/156 (0%)		0/157 (0%)		0/156 (0%)		5/156 (3.2%)		11/157 (7%)		2/156 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.