An Efficacy, Safety, and Tolerability Study of Canagliflozin in Patients With Type 2 Diabetes Mellitus Who Have Moderate Renal Impairment

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01064414
• Collaborator: (none)
• Enrollment: 272
• Locations: 109
• Arms: 3
• Duration (Months): 26
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

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 have reduced kidney function.

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

Detailed Description

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), parallel-group, 3-arm (patients will be assigned to 1 of 3 treatment groups) multicenter study to determine the efficacy, safety, and tolerability of 2 different doses of canagliflozin (100 mg and 300 mg) compared to placebo (a pill that looks like all the other treatments but has no real medicine) in patients with type 2 diabetes mellitus (T2DM) who have renal impairment (reduced kidney function) and who are not achieving an adequate response from current therapy to control their diabetes. Canagliflozin (also referred to as JNJ-28431754) is a drug that is being tested to see if it may be useful in treating patients diagnosed with T2DM. Approximately 240 patients will participate in the study for approximately 63 to 72 weeks, depending on the length of the pretreatment phase. The study will consist of a pretreatment phase, a 52 week double blind treatment phase, and a posttreatment phase. During the pretreatment phase, screening evaluations will be performed to see if patients meet the entry criteria for the study. In addition, routine clinical procedures will be performed (physical examination, vital signs measurements, and an electrocardiogram [ECG]), a blood and urine sample will be collected for routine clinical laboratory tests, and all antihyperglycemic therapy taken by patients will be reviewed. Patients who meet entrance criteria for the study and who currently take a stable antihyperglycemic agent (AHA) regimen according to the local prescribing information will be eligible for inclusion in the study. Patients who meet entrance criteria for the study but who are not taking a stable AHA regimen according to the local prescribing information will enter an AHA adjustment period that may last for up to 12 weeks. Patients will receive once daily treatment with study drug in addition to their current stable diabetes regimen (eg, diet, exercise, and medication therapy). Patients will continue to take their assigned treatment for 52 weeks (includes a 26-week core double-blind treatment period and a 26-week extension double-blind treatment period). During the study, if a patient's blood sugar remains high despite treatment with study drug in combination with their other antidiabetic agents, the study physician will modify the patient's treatment. If patients take insulin and experience low blood sugar (hypoglycemia), the dose of insulin may be modified. During the study, patients will be monitored for safety by review of adverse events, results from safety laboratory tests (including chemistry, hematology, and urinalysis), ECGs, vital signs measurements, body weight, physical examinations, self-monitored blood glucose, and collection of potential hypoglycemic episodes reported by patients on diary cards. The safety of patients in this study will also be monitored by a company internal Medical Safety Review Committee (MSRC). An Independent Data Monitoring Committee (IDMC) will evaluate cardiovascular (CV) events that are reported across the entire clinical development program for canagliflozin. Patients who complete the Week 52 visit or who discontinue treatment early and are withdrawn from the study will have end-of-study evaluations performed and a follow-up telephone interview conducted by study personnel approximately 30 days (but no more than 42 days) after the last dose of study drug to collect any serious adverse events that occurred since their last study visit. The primary outcome measures in the study are to assess the effect of canagliflozin relative to placebo on hemoglobin A1c (HbA1c, a blood test used to measure the control of diabetes) after 26 weeks of treatment and to assess the safety and tolerability of canagliflozin from time of signed informed consent to study end (includes up to 30 days following the last dose of study drug). All patients will take a single-blind placebo capsule once daily for 2 weeks before randomization to double-blind study drug. After randomization, patients will take one capsule of canagliflozin (either 100 mg or 300 mg) or matching placebo orally (by mouth) with liquid once daily for 52 weeks before the first meal each day except on days when fasting or pharmacokinetic blood samples are collected in which case study drug will be taken after the visit immediately before the patient's next meal.

Study Design

• Study Type: Interventional
• Actual Enrollment: 272 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, 3-Arm, Parallel-Group, 26-Week, Multicenter Study With a 26-Week Extension, to Evaluate the Efficacy, Safety and Tolerability of Canagliflozin in the Treatment of Subjects With Type 2 Diabetes Mellitus Who Have Moderate Renal Impairment
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Aug 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.	Drug: Canagliflozin; One 100 mg or 300 mg over-encapsulated tablet orally (by mouth) once daily for 52 weeks in addition to the patient's AHA regimen used in accordance with local prescribing information
Experimental: Canagliflozin 300 mg Each patient will receive 300 mg of canagliflozin once daily for 52 weeks.	Drug: Canagliflozin; One 100 mg or 300 mg over-encapsulated tablet orally (by mouth) once daily for 52 weeks in addition to the patient's AHA regimen used in accordance with local prescribing information
Placebo Comparator: Placebo Each patient will receive matching placebo once daily for 52 weeks.	Drug: Placebo; One matching placebo capsule orally once daily for 52 weeks in addition to the patient's AHA regimen used in accordance with local prescribing information

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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with T2DM not on an AHA or on any AHA in monotherapy or combination therapy (including oral or non oral agents)

• Patients with reduced kidney function

Exclusion Criteria:

• History of diabetic ketoacidosis, type 1 diabetes mellitus (T1DM), pancreas or beta cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy

• Have proliferative diabetic retinopathy for which treatment is planned during the course of the study

• Kidney disease that required treatment with immunosuppressive therapy, history of dialysis or kidney transplant, presence of nephrotic syndrome (eg, severe proteinuria with hypoalbuminemia and/or edema), or inflammatory kidney disease

• Receiving anti hypertensive or anti-hyperlipidemic therapy not on a stable regimen

• History of a severe hypoglycemic episode within 6 months before screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Concord	California	United States
2		Fountain Valley	California	United States
3		San Diego	California	United States
4		Denver	Colorado	United States
5		Pembroke Pines	Florida	United States
6		Tampa	Florida	United States
7		West Palm Beach	Florida	United States
8		Augusta	Georgia	United States
9		Nampa	Idaho	United States
10		Baton Rouge	Louisiana	United States
11		Jackson	Mississippi	United States
12		Picayune	Mississippi	United States
13		Chesterfield	Missouri	United States
14		Las Vegas	Nevada	United States
15		Albuquerque	New Mexico	United States
16		Durham	North Carolina	United States
17		Canal Fulton	Ohio	United States
18		Cincinnati	Ohio	United States
19		Columbus	Ohio	United States
20		Zanesville	Ohio	United States
21		Oklahoma City	Oklahoma	United States
22		Meridian	Pennsylvania	United States
23		Pittsburgh	Pennsylvania	United States
24		North Charleston	South Carolina	United States
25		Salt Lake City	Utah	United States
26		Fairfax	Virginia	United States
27		Camperdown		Australia
28		Gosford		Australia
29		Parkville		Australia
30		Reservoir		Australia
31		Aalst		Belgium
32		Bonheiden		Belgium
33		Brussels		Belgium
34		Liège		Belgium
35		Sint-Niklaas		Belgium
36		Turnhout		Belgium
37		Sao Paulo		Brazil
38		São Paulo		Brazil
39		Vancouver	British Columbia	Canada
40		Victoria	British Columbia	Canada
41		Antigonish	Nova Scotia	Canada
42		Sydney	Nova Scotia	Canada
43		Hamilton	Ontario	Canada
44		London	Ontario	Canada
45		Smiths Falls	Ontario	Canada
46		Thornhill	Ontario	Canada
47		Montreal	Quebec	Canada
48		Calgary		Canada
49		Corbeil Essonnes		France
50		La Rochelle Cedex 1 Poitou-Cha		France
51		Le Creusot		France
52		Nantes N/A		France
53		Pierre Benite		France
54		Vandoeuvre Les Nancy		France
55		Venissieux		France
56		Dormagen		Germany
57		Dortmund		Germany
58		Dresden		Germany
59		Einbeck		Germany
60		Freiburg		Germany
61		Kassel		Germany
62		München		Germany
63		Schkeuditz		Germany
64		Würzburg		Germany
65		Aurangabad		India
66		Madurai		India
67		Pune		India
68		Seognam-Si, Kyungki-Do		Korea, Republic of
69		Seoul		Korea, Republic of
70		Daugavpils		Latvia
71		Ogre		Latvia
72		Riga		Latvia
73		Jalan Cheras N/A		Malaysia
74		Kajang		Malaysia
75		Kuala Lumpur N/A		Malaysia
76		Pulau Pinang		Malaysia
77		Aguascalientes		Mexico
78		Culiacan		Mexico
79		Morelia		Mexico
80		Zapopan		Mexico
81		Auckland		New Zealand
82		Christchurch		New Zealand
83		Dunedin Nz		New Zealand
84		Nz		New Zealand
85		Lask		Poland
86		Lublin		Poland
87		Warszawa		Poland
88		Bucharest		Romania
89		Targoviste		Romania
90		Chelyabinsk		Russian Federation
91		Kirov		Russian Federation
92		Kursk		Russian Federation
93		Moscow		Russian Federation
94		Nizhny Novgorod		Russian Federation
95		Petrozavodsk		Russian Federation
96		Rostov-On-Don		Russian Federation
97		Saint Petersburg		Russian Federation
98		St Petersburg		Russian Federation
99		Yaroslavl		Russian Federation
100		Parow, Cape Town		South Africa
101		Pretoria		South Africa
102		Somerset West		South Africa
103		Barcelona		Spain
104		Ciudad Real		Spain
105		Madrid N/A		Spain
106		Madrid		Spain
107		San Sebastian De Los Reyes		Spain
108		Santa Cruz De Tenerife		Spain
109		Valencia		Spain

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: NCT01064414
• Other Study ID Numbers: CR017008; 28431754DIA3004
• First Posted: Feb 8, 2010
• Last Update Posted: Aug 14, 2013
• Last Verified: Aug 1, 2013

• Keywords provided by Janssen Research & Development, LLC: Canagliflozin; JNJ 28431754; Placebo; Sodium-Glucose Transporter 2; hemoglobin A1c protein, Blood Glucose; reduced kidney function, Type 2 diabetes mellitus
• Additional relevant MeSH terms: Renal Insufficiency; Diabetes Mellitus; Diabetes Mellitus, Type 2; Canagliflozin

Study Results

Participant Flow

Recruitment Details	This study evaluated the efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus and moderate renal impairment. The study was conducted between 02 March 2010 and 19 January 2012 and recruited patients from 89 study centers located in 19 countries worldwide.
Pre-assignment Detail	272 patients were randomly allocated to the 3 treatment arms. 269 patients received at least 1 dose of study drug and were included in the modified intent-to-treat (mITT) analysis set and safety analysis set. Participant flow is presented in two parts: for Baseline to Week 26 as "Core Period", and for Week 26 to Week 52 as "Extension Period".

Arm/Group Title	Placebo	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 52 weeks. Data are presented for Baseline to Week 26 (Core Period) and for Week 26 to 52 (Extension Period).	Each patient received 100 mg of canagliflozin once daily for 52 weeks. Data are presented for Baseline to Week 26 (Core Period) and for Week 26 to 52 (Extension Period).	Each patient received 300 mg of canagliflozin once daily for 52 weeks.Data are presented for Baseline to Week 26 (Core Period) and for Week 26 to 52 (Extension Period).
Period Title: Core Period: Baseline to Week 26
STARTED	90	90	89
COMPLETED	77	75	82
NOT COMPLETED	13	15	7
Period Title: Core Period: Baseline to Week 26
STARTED	76	72	81
COMPLETED	64	67	76
NOT COMPLETED	12	5	5

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.	Each patient received 100 mg of canagliflozin once daily for 52 weeks.	Each patient received 300 mg of canagliflozin once daily for 52 weeks.	Total of all reporting groups
Overall Participants	90	90	89	269
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	27 30%	24 26.7%	32 36%	83 30.9%
>=65 years	63 70%	66 73.3%	57 64%	186 69.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.2 (8.4)	69.5 (8.2)	67.9 (8.24)	68.5 (8.28)
Sex: Female, Male (Count of Participants)
Female	33 36.7%	32 35.6%	41 46.1%	106 39.4%
Male	57 63.3%	58 64.4%	48 53.9%	163 60.6%
Region of Enrollment (participants) [Number]
AUSTRALIA	3 3.3%	6 6.7%	5 5.6%	14 5.2%
BELGIUM	5 5.6%	1 1.1%	6 6.7%	12 4.5%
BRAZIL	4 4.4%	4 4.4%	5 5.6%	13 4.8%
CANADA	7 7.8%	11 12.2%	3 3.4%	21 7.8%
FRANCE	7 7.8%	5 5.6%	4 4.5%	16 5.9%
GERMANY	6 6.7%	10 11.1%	2 2.2%	18 6.7%
INDIA	3 3.3%	3 3.3%	3 3.4%	9 3.3%
ITALY	4 4.4%	1 1.1%	1 1.1%	6 2.2%
LATVIA	2 2.2%	1 1.1%	4 4.5%	7 2.6%
MALAYSIA	2 2.2%	4 4.4%	8 9%	14 5.2%
MEXICO	0 0%	2 2.2%	2 2.2%	4 1.5%
NEW ZEALAND	7 7.8%	2 2.2%	5 5.6%	14 5.2%
POLAND	5 5.6%	5 5.6%	4 4.5%	14 5.2%
ROMANIA	2 2.2%	1 1.1%	2 2.2%	5 1.9%
RUSSIAN FEDERATION	10 11.1%	11 12.2%	9 10.1%	30 11.2%
SOUTH AFRICA	2 2.2%	3 3.3%	1 1.1%	6 2.2%
SOUTH KOREA	1 1.1%	1 1.1%	0 0%	2 0.7%
SPAIN	4 4.4%	5 5.6%	8 9%	17 6.3%
UNITED STATES	16 17.8%	14 15.6%	17 19.1%	47 17.5%

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.	Each patient received canagliflozin 100 mg once daily for 52 weeks.	Each patient received canagliflozin 300 mg once daily for 52 weeks.
Measure Participants	87	88	89
Least Squares Mean (Standard Error) [Percent]	-0.03 (0.090)	-0.33 (0.090)	-0.44 (0.089)

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	0.012
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.529 to -0.066
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.117
	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	-0.40
	Confidence Interval	(2-Sided) 95%; -0.635 to -0.174
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.117
	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.	Each patient received canagliflozin 100 mg once daily for 52 weeks.	Each patient received canagliflozin 300 mg once daily for 52 weeks.
Measure Participants	87	88	89
Number [Percentage of patients]	17.2	27.3	32.6

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	0.227
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.66
	Confidence Interval	(2-Sided) 95%; 0.73 to 3.77
	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	0.017
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.69
	Confidence Interval	(2-Sided) 95%; 1.19 to 6.04
	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.	Each patient received canagliflozin 100 mg once daily for 52 weeks.	Each patient received canagliflozin 300 mg once daily for 52 weeks.
Measure Participants	88	90	88
Least Squares Mean (Standard Error) [mg/dL]	0.49 (5.089)	-14.9 (5.089)	-11.7 (5.099)

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	0.021
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-15.4
	Confidence Interval	(2-Sided) 95%; -28.45 to -2.307
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.638
	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	0.069
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-12.2
	Confidence Interval	(2-Sided) 95%; -25.36 to 0.962
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.683
	Estimation Comments

Adverse Events

Time Frame	Adverse events data were collected for the duration of study (52 weeks).
Adverse Event Reporting Description	The total number of adverse events listed in the "Other (non-Serious) Adverse Events" table is 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. Data are presented for Baseline to Week 26.		Each patient received 100 mg of canagliflozin once daily for 52 weeks. Data are presented for Baseline to Week 26.		Each patient received 300 mg of canagliflozin once daily for 52 weeks. Data are presented for Baseline to Week 26.		Each patient received matching placebo once daily for 52 weeks. Data are presented for Baseline to Week 52.		Each patient received 100 mg of canagliflozin once daily for 52 weeks. Data are presented for Baseline to Week 52.		Each patient received 300 mg of canagliflozin once daily for 52 weeks. 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	16/90 (17.8%)		10/90 (11.1%)		10/89 (11.2%)		24/90 (26.7%)		18/90 (20%)		21/89 (23.6%)
Blood and lymphatic system disorders
Iron deficiency anaemia	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Cardiac disorders
Acute coronary syndrome	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Cardiac arrest	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Cardiac failure congestive	1/90 (1.1%)		0/90 (0%)		1/89 (1.1%)		1/90 (1.1%)		0/90 (0%)		2/89 (2.2%)
Coronary artery disease	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		1/89 (1.1%)
Myocardial infarction	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		2/90 (2.2%)		0/90 (0%)		2/89 (2.2%)
Myocardial ischaemia	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		1/90 (1.1%)		1/90 (1.1%)		0/89 (0%)
Ventricular fibrillation	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Coronary artery insufficiency	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Cor pulmonale	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Cardiac failure acute	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Acute myocardial infarction	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		1/90 (1.1%)		0/89 (0%)
Angina pectoris	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Angina unstable	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Atrial fibrilation	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		2/90 (2.2%)		0/89 (0%)
Eye disorders
Glaucoma	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Cataract	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Gastrointestinal disorders
Diarrhoea	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Intestinal perforation	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
General disorders
Non-cardiac chest pain	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Oedema peripheral	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Hepatobiliary disorders
Bile duct stone	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Infections and infestations
Appendicitis perforated	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Campylobacter intestinal infection	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		0/90 (0%)		0/90 (0%)		0/89 (0%)
Infected skin ulcer	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Infective exacerbation of chronic obstructive airways disease	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Lower respiratory tract infection	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Pneumonia	2/90 (2.2%)		0/90 (0%)		0/89 (0%)		2/90 (2.2%)		0/90 (0%)		0/89 (0%)
Sepsis	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Septic shock	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Appendicitis	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Cellulitis	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Gastroenteritis	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Lobar pneumonia	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Campylobacter gastroenteritis	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Injury, poisoning and procedural complications
Fibula fracture	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Joint dislocation	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Splenic rupture	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Tibia fracture	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Wound complication	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Investigations
Blood creatinine increased	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Troponin increased	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Metabolism and nutrition disorders
Dehydration	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Hypoglycaemia	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		1/89 (1.1%)
Diabetic complications	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small cell lung cancer metastatic	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Nervous system disorders
Carotid artery stenosis	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Transient ischaemic attack	1/90 (1.1%)		1/90 (1.1%)		0/89 (0%)		1/90 (1.1%)		1/90 (1.1%)		0/89 (0%)
Cerebral infarction	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Cerebrovascular accident	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Renal and urinary disorders
Bladder neck obstruction	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Renal artery stenosis	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Renal failure	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		2/90 (2.2%)		0/90 (0%)		0/89 (0%)
Renal failure acute	0/90 (0%)		1/90 (1.1%)		1/89 (1.1%)		1/90 (1.1%)		1/90 (1.1%)		1/89 (1.1%)
Renal impairment	1/90 (1.1%)		0/90 (0%)		1/89 (1.1%)		1/90 (1.1%)		0/90 (0%)		1/89 (1.1%)
Neophrolithiasis	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Urinary retention	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/90 (0%)		1/90 (1.1%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Bronchospasm	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Pulmonary embolism	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Acute respiratory failure	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Pulmonary fibrosis	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Respiratory failure	0/90 (0%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Diabetic foot	0/90 (0%)		1/90 (1.1%)		1/89 (1.1%)		1/90 (1.1%)		1/90 (1.1%)		1/89 (1.1%)
Skin necrosis	0/90 (0%)		0/90 (0%)		0/89 (0%)		0/90 (0%)		1/90 (1.1%)		0/89 (0%)
Vascular disorders
Arteritis	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Deep vein thrombosis	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		1/90 (1.1%)		0/90 (0%)		1/89 (1.1%)
Femoral arterial stenosis	0/90 (0%)		0/90 (0%)		1/89 (1.1%)		0/90 (0%)		0/90 (0%)		1/89 (1.1%)
Hypertension	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
Hypotension	1/90 (1.1%)		0/90 (0%)		0/89 (0%)		1/90 (1.1%)		0/90 (0%)		0/89 (0%)
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	27/90 (30%)		21/90 (23.3%)		33/89 (37.1%)		46/90 (51.1%)		46/90 (51.1%)		48/89 (53.9%)
Gastrointestinal disorders
Diarrhoea	5/90 (5.6%)		3/90 (3.3%)		4/89 (4.5%)		9/90 (10%)		4/90 (4.4%)		4/89 (4.5%)
General disorders
Fatigue	4/90 (4.4%)		0/90 (0%)		4/89 (4.5%)		5/90 (5.6%)		1/90 (1.1%)		5/89 (5.6%)
Oedema peripheral	4/90 (4.4%)		2/90 (2.2%)		3/89 (3.4%)		6/90 (6.7%)		5/90 (5.6%)		6/89 (6.7%)
Infections and infestations
Nasopharyngitis	10/90 (11.1%)		3/90 (3.3%)		7/89 (7.9%)		13/90 (14.4%)		5/90 (5.6%)		9/89 (10.1%)
Urinary tract infection	5/90 (5.6%)		4/90 (4.4%)		7/89 (7.9%)		6/90 (6.7%)		4/90 (4.4%)		12/89 (13.5%)
Bronchitis	3/90 (3.3%)		4/90 (4.4%)		3/89 (3.4%)		1/90 (1.1%)		5/90 (5.6%)		5/89 (5.6%)
Influenza	3/90 (3.3%)		3/90 (3.3%)		2/89 (2.2%)		6/90 (6.7%)		3/90 (3.3%)		3/89 (3.4%)
Upper respiratory tract	1/90 (1.1%)		3/90 (3.3%)		1/89 (1.1%)		1/90 (1.1%)		5/90 (5.6%)		4/89 (4.5%)
Metabolism and nutrition disorders
Hypoglycaemia	4/90 (4.4%)		13/90 (14.4%)		10/89 (11.2%)		4/90 (4.4%)		18/90 (20%)		20/89 (22.5%)
Vitamin D deficiency	5/90 (5.6%)		0/90 (0%)		1/89 (1.1%)		4/90 (4.4%)		2/90 (2.2%)		1/89 (1.1%)
Hyperkalaemia	3/90 (3.3%)		2/90 (2.2%)		1/89 (1.1%)		5/90 (5.6%)		3/90 (3.3%)		1/89 (1.1%)
Hyperglycaemia	4/90 (4.4%)		2/90 (2.2%)		2/89 (2.2%)		5/90 (5.6%)		2/90 (2.2%)		2/89 (2.2%)
Musculoskeletal and connective tissue disorders
Back pain	5/90 (5.6%)		0/90 (0%)		2/89 (2.2%)		5/90 (5.6%)		1/90 (1.1%)		4/89 (4.5%)
Arthralgia	2/90 (2.2%)		4/90 (4.4%)		2/89 (2.2%)		3/90 (3.3%)		5/90 (5.6%)		3/89 (3.4%)
Nervous system disorders
Dizziness	0/90 (0%)		1/90 (1.1%)		5/89 (5.6%)		2/90 (2.2%)		1/90 (1.1%)		5/89 (5.6%)
Headache	3/90 (3.3%)		2/90 (2.2%)		2/89 (2.2%)		5/90 (5.6%)		3/90 (3.3%)		3/89 (3.4%)
Vascular disorders
Hypotension	0/90 (0%)		1/90 (1.1%)		6/89 (6.7%)		3/90 (3.3%)		1/90 (1.1%)		6/89 (6.7%)

Limitations/Caveats

[Not Specified]

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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.