The CANTATA-MP Trial (CANagliflozin Treatment and Trial Analysis - Metformin and Pioglitazone)

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01106690
• Collaborator: (none)
• Enrollment: 344
• Locations: 83
• Arms: 3
• Duration (Months): 25
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.2

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 receving treatment with metformin and pioglitazone and have inadequate glycemic (blood sugar) control.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Placebo; Drug: Canagliflozin; Drug: Sitagliptin; Drug: Metformin; Drug: Pioglitazone	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), 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 pioglitazone to control their diabetes. Approximately 360 patients with T2DM who are receiving combination therapy with metformin and pioglitazone will receive the addition of once-daily treatment with canagliflozin (100 mg or 300 mg) or placebo capsules for 26 weeks followed by a 26-week extension period where patients treated with canagliflozin (100 mg or 300 mg) will continue treatment for an additional 26 weeks and patients treated with placebo will be switched to active double-blind treatment with sitagliptin 100 mg, an antihyperglycemic agent administered once-daily for 26 weeks. In addition, all patients will take protocol specified stable doses of metformin and pioglitazone along with assigned study drug for the duration of the study. Patients will participate in the study for approximately 59 to 78 weeks. During the study, if a patient's fasting blood sugar remains high despite treatment with study drug, the patient will receive treatment with glimepiride (rescue therapy) in accordance 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 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. 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) for 52 weeks OR placebo for 26 weeks switched to double-blind sitagliptin 100 mg for 26 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 344 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 Pioglitazone Therapy
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Other: Placebo/Sitagliptin Each patient will receive matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients will be switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Drug: Placebo; One matching placebo capsule orally (by mouth) once daily for 26 weeks with stable doses of metformin and pioglitazone.; Drug: Sitagliptin; One 100 mg over-encapsulated tablet orally once daily beginning at Week 26 until Week 52 with stable doses of metformin and pioglitazone.; Drug: Metformin; The patient's stable dose of metformin background therapy should be continued throughout the study.; Drug: Pioglitazone; The patient's stable dose of pioglitazone background therapy should be continued throughout the study.
Experimental: Canagliflozin 100 mg Each patient will receive 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Drug: Canagliflozin; One 100 mg or 300 mg over-encapsulated tablet orally once daily for 52 weeks with stable doses of metformin and pioglitazone.; Drug: Metformin; The patient's stable dose of metformin background therapy should be continued throughout the study.; Drug: Pioglitazone; The patient's stable dose of pioglitazone background 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 stable doses of metformin and pioglitazone.	Drug: Canagliflozin; One 100 mg or 300 mg over-encapsulated tablet orally once daily for 52 weeks with stable doses of metformin and pioglitazone.; Drug: Metformin; The patient's stable dose of metformin background therapy should be continued throughout the study.; Drug: Pioglitazone; The patient's stable dose of pioglitazone background 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. Change in Homeostasis Model Assessment (HOMA2-%B) From Baseline to Week 26 [Day 1 (Baseline) and Week 26]

   HOMA2-%B is a measure of beta cell function (the cells in the pancreas that produce and store insulin). The table below shows the least-squares (LS) mean change in HOMA2-%B 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.

4. 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.

5. 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.

6. 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.

7. 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 PPAR gamma agent ((pioglitazone or rosiglitazone) and another anti-diabetes agent (metformin)

• Patients in the study must have a HbA1c between >=7 and <=10.5% and 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		Anniston	Alabama	United States
2		Phoenix	Arizona	United States
3		Tucson	Arizona	United States
4		Little Rock	Arkansas	United States
5		Burlingame	California	United States
6		Encinitas	California	United States
7		Fullerton	California	United States
8		Roseville	California	United States
9		Santa Ana	California	United States
10		Wes Hills	California	United States
11		Colorado Springs	Colorado	United States
12		Bartow	Florida	United States
13		Hollywood	Florida	United States
14		Jacksonville	Florida	United States
15		Pembroke Pines	Florida	United States
16		Des Moines	Iowa	United States
17		Baton Rouge	Louisiana	United States
18		Chaska	Minnesota	United States
19		Picayune	Mississippi	United States
20		Billings	Montana	United States
21		Charlotte	North Carolina	United States
22		Hickory	North Carolina	United States
23		Raleigh	North Carolina	United States
24		Dublin	Ohio	United States
25		Perrysburg	Ohio	United States
26		Tulsa	Oklahoma	United States
27		Yukon	Oklahoma	United States
28		Bensalem	Pennsylvania	United States
29		Bristol	Tennessee	United States
30		Kingsport	Tennessee	United States
31		Nashville	Tennessee	United States
32		Arlington	Texas	United States
33		Dallas	Texas	United States
34		Grand Prairie	Texas	United States
35		Houston	Texas	United States
36		New Braunfels	Texas	United States
37		San Antonio	Texas	United States
38		Falls Church	Virginia	United States
39		Virginia Beach	Virginia	United States
40		Federal Way	Washington	United States
41		Selah	Washington	United States
42		Bathurst	New Brunswick	Canada
43		Moncton	New Brunswick	Canada
44		Grand Falls-Windsor	Newfoundland and Labrador	Canada
45		Brampton	Ontario	Canada
46		Hamilton	Ontario	Canada
47		Ottawa	Ontario	Canada
48		Smiths Falls	Ontario	Canada
49		Thornhill	Ontario	Canada
50		Drummondville	Quebec	Canada
51		Calgary		Canada
52		Mount Pearl		Canada
53		Truro		Canada
54		Kuopio		Finland
55		Oulu		Finland
56		Turku		Finland
57		Bondy Cedex		France
58		Le Creusot		France
59		Narbonne Cedex		France
60		Aschaffenburg		Germany
61		Mainz		Germany
62		Neuwied		Germany
63		Schkeuditz		Germany
64		Athens		Greece
65		Thessalonikis		Greece
66		Thessaloniki		Greece
67		Ahmedabad		India
68		Belgaum		India
69		Chennai		India
70		Coimbatore		India
71		Jaipur		India
72		Nagpur		India
73		Chihuahua		Mexico
74		Ciudad Juarez		Mexico
75		Durango		Mexico
76		Mexico		Mexico
77		Almería		Spain
78		Madrid		Spain
79		Sevilla		Spain
80		Bangkok		Thailand
81		Khon Kaen		Thailand
82		Antrim		United Kingdom
83		Belfast		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: NCT01106690
• Other Study ID Numbers: CR017032; 28431754DIA3012
• First Posted: Apr 20, 2010
• Last Update Posted: Jul 15, 2013
• Last Verified: Jun 1, 2013

• Keywords provided by Janssen Research & Development, LLC: Canagliflozin; Placebo; Sitagliptin (Januvia); Metformin; Pioglitazone (Actos); Hemoglobin A1c; Type 2 diabetes mellitus
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Pioglitazone; Sitagliptin Phosphate; 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 pioglitazone. The study was conducted between 13 April 2010 and 20 November 2011 and recruited patients from 74 study centers in 11 countries worldwide.
Pre-assignment Detail	344 patients were randomly allocated to the 3 treatment arms. 342 patients received at least 1 dose of study drug and were included in the modified intent-to-treat (mITT) analysis set (used for the Week 26 efficacy analysis) and safety analysis set (used for the Week 26 and Week 52 safety analyses).

Arm/Group Title	Placebo/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
Period Title: Core Period: Baseline to Week 26
STARTED	115	113	114
COMPLETED	91	104	101
NOT COMPLETED	24	9	13
Period Title: Core Period: Baseline to Week 26
STARTED	90	103	96
COMPLETED	78	96	89
NOT COMPLETED	12	7	7

Baseline Characteristics

Arm/Group Title	Placebo/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg	Total
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Total of all reporting groups
Overall Participants	115	113	114	342
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	83 72.2%	83 73.5%	83 72.8%	249 72.8%
>=65 years	32 27.8%	30 26.5%	31 27.2%	93 27.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.3 (9.56)	56.7 (10.36)	57 (10.19)	57.4 (10.03)
Sex: Female, Male (Count of Participants)
Female	39 33.9%	36 31.9%	51 44.7%	126 36.8%
Male	76 66.1%	77 68.1%	63 55.3%	216 63.2%
Region of Enrollment (participants) [Number]
CANADA	24 20.9%	22 19.5%	21 18.4%	67 19.6%
FINLAND	7 6.1%	3 2.7%	3 2.6%	13 3.8%
FRANCE	1 0.9%	0 0%	1 0.9%	2 0.6%
GERMANY	7 6.1%	5 4.4%	7 6.1%	19 5.6%
GREECE	0 0%	0 0%	1 0.9%	1 0.3%
INDIA	10 8.7%	10 8.8%	5 4.4%	25 7.3%
MEXICO	7 6.1%	3 2.7%	11 9.6%	21 6.1%
SPAIN	8 7%	5 4.4%	2 1.8%	15 4.4%
THAILAND	5 4.3%	8 7.1%	4 3.5%	17 5%
UNITED KINGDOM	3 2.6%	2 1.8%	3 2.6%	8 2.3%
UNITED STATES	43 37.4%	55 48.7%	56 49.1%	154 45%

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/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
Measure Participants	114	113	112
Least Squares Mean (Standard Error) [Percent]	-0.26 (0.069)	-0.89 (0.069)	-1.03 (0.070)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	-0.62
	Confidence Interval	(2-Sided) 95%; -0.811 to -0.437
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.095
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	-0.76
	Confidence Interval	(2-Sided) 95%; -0.951 to -0.575
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.096
	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/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
Measure Participants	114	113	112
Number [Percentage of patients]	32.5	46.9	64.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.40
	Confidence Interval	() 95%; 1.26 to 4.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	5.38
	Confidence Interval	(2-Sided) 95%; 2.73 to 10.60
	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/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
Measure Participants	114	113	112
Least Squares Mean (Standard Error) [mg/dL]	2.54 (2.785)	-26.8 (2.796)	-33.2 (2.817)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	-29.4
	Confidence Interval	(2-Sided) 95%; -36.96 to -21.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.857
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	-35.7
	Confidence Interval	(2-Sided) 95%; -43.30 to -28.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.861
	Estimation Comments

4. Secondary Outcome

Title	Change in Homeostasis Model Assessment (HOMA2-%B) From Baseline to Week 26
Description	HOMA2-%B is a measure of beta cell function (the cells in the pancreas that produce and store insulin). The table below shows the least-squares (LS) mean change in HOMA2-%B 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/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
Measure Participants	100	103	105
Least Squares Mean (Standard Error) [HOMA2-%B]	0.91 (1.833)	15.19 (1.809)	18.14 (1.790)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	14.28
	Confidence Interval	(2-Sided) 95%; 9.315 to 19.236
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.521
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	17.23
	Confidence Interval	(2-Sided) 95%; 12.293 to 22.166
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.509
	Estimation Comments

5. 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/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
Measure Participants	114	113	112
Least Squares Mean (Standard Error) [Percent change]	-0.1 (0.3)	-2.8 (0.3)	-3.8 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	-2.7
	Confidence Interval	(2-Sided) 95%; -3.6 to -1.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	-3.7
	Confidence Interval	(2-Sided) 95%; -4.6 to -2.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4
	Estimation Comments

6. 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/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
Measure Participants	114	113	112
Least Squares Mean (Standard Error) [mmHg]	-1.24 (1.033)	-5.30 (1.036)	-4.70 (1.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-4.07
	Confidence Interval	(2-Sided) 95%; -6.879 to -1.251
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.430
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, Canagliflozin 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-3.46
	Confidence Interval	(2-Sided) 95%; -6.281 to -0.643
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.433
	Estimation Comments

7. 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/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
Measure Participants	105	108	109
Least Squares Mean (Standard Error) [Percent change]	15.2 (4.1)	3.2 (4.1)	-1.7 (4.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-12.1
	Confidence Interval	(2-Sided) 95%; -12.1 to -0.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.7
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, Canagliflozin 300 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	-16.9
	Confidence Interval	(2-Sided) 95%; -28.1 to -5.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.7
	Estimation Comments

8. 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/Sitagliptin	Canagliflozin 100 mg	Canagliflozin 300 mg
Arm/Group Description	Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.	Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.	Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
Measure Participants	105	107	109
Least Squares Mean (Standard Error) [Percent change]	2.4 (1.4)	7.2 (1.3)	8.9 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, Canagliflozin 100 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least-Squares Mean Difference
	Estimated Value	4.8
	Confidence Interval	(2-Sided) 95%; 1.2 to 8.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.9
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Sitagliptin, 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	6.5
	Confidence Interval	(2-Sided) 95%; 2.8 to 10.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.9
	Estimation Comments

Adverse Events

Time Frame	Adverse event 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 are based upon a cut-off of greater than or equal to 5 percent of patients experiencing the adverse event in any treatment arm either during the 26-week period or entire 52-week period.
Arm/Group Title	Placebo/Sitagliptin: Baseline to Week 26		Canagliflozin 100 mg: Baseline to Week 26		Canagliflozin 300 mg: Baseline to Week 26		Placebo/Sitagliptin: 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 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52. Data are presented for Baseline to Week 26.		Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone. Data are presented for Baseline to Week 26.		Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone. Data are presented for Baseline to Week 26.		Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52. Data are presented for Baseline to Week 52.		Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone. Data are presented for Baseline to Week 52.		Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone. Data are presented for Baseline to Week 52.
All Cause Mortality
	Placebo/Sitagliptin: Baseline to Week 26		Canagliflozin 100 mg: Baseline to Week 26		Canagliflozin 300 mg: Baseline to Week 26		Placebo/Sitagliptin: 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/Sitagliptin: Baseline to Week 26		Canagliflozin 100 mg: Baseline to Week 26		Canagliflozin 300 mg: Baseline to Week 26		Placebo/Sitagliptin: 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	5/115 (4.3%)		3/113 (2.7%)		4/114 (3.5%)		6/115 (5.2%)		8/113 (7.1%)		7/114 (6.1%)
Cardiac disorders
Acute coronary syndrome	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Gastrointestinal disorders
Dyspepsia	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
General disorders
Chest pain	0/115 (0%)		1/113 (0.9%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Hepatobiliary disorders
Cholecystitis acute	0/115 (0%)		1/113 (0.9%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Infections and infestations
Anal abscess	0/115 (0%)		1/113 (0.9%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Escherichia bacteraemia	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Gastrointestinal infection	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Osteomyelitis	0/115 (0%)		0/113 (0%)		1/114 (0.9%)		0/115 (0%)		0/113 (0%)		1/114 (0.9%)
Sepsis syndrome	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Bacterial Sepsis	0/115 (0%)		0/113 (0%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Bronchopneumonia	0/115 (0%)		0/113 (0%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Cellulitis	0/115 (0%)		0/113 (0%)		0/114 (0%)		0/115 (0%)		0/113 (0%)		1/114 (0.9%)
Injury, poisoning and procedural complications
Concussion	0/115 (0%)		0/113 (0%)		1/114 (0.9%)		0/115 (0%)		0/113 (0%)		1/114 (0.9%)
Laceration	0/115 (0%)		0/113 (0%)		1/114 (0.9%)		0/115 (0%)		0/113 (0%)		1/114 (0.9%)
Periprosthetic fracture	0/115 (0%)		1/113 (0.9%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Subdural haematoma	0/115 (0%)		0/113 (0%)		1/114 (0.9%)		0/115 (0%)		0/113 (0%)		1/114 (0.9%)
Tibia fracture	0/115 (0%)		0/113 (0%)		0/114 (0%)		0/115 (0%)		0/113 (0%)		1/114 (0.9%)
Investigations
Arteriogram coronary	0/115 (0%)		0/113 (0%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Musculoskeletal and connective tissue disorders
Spinal column stenosis	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Dupuytren's contracture	0/115 (0%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Osteoarthritis	0/115 (0%)		0/113 (0%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/115 (0%)		0/113 (0%)		1/114 (0.9%)		0/115 (0%)		0/113 (0%)		1/114 (0.9%)
Nervous system disorders
Cerebrovascular accident	0/115 (0%)		0/113 (0%)		0/114 (0%)		0/115 (0%)		0/113 (0%)		1/114 (0.9%)
Dizziness postural	0/115 (0%)		0/113 (0%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Reproductive system and breast disorders
Pelvic prolapse	0/115 (0%)		0/113 (0%)		0/114 (0%)		0/115 (0%)		1/113 (0.9%)		0/114 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Dyspnoea	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Hypercapnia	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Restrictive pulmonary disease	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		0/113 (0%)		0/114 (0%)
Vascular disorders
Hypotension	1/115 (0.9%)		0/113 (0%)		0/114 (0%)		1/115 (0.9%)		1/113 (0.9%)		0/114 (0%)
Other (Not Including Serious) Adverse Events
	Placebo/Sitagliptin: Baseline to Week 26		Canagliflozin 100 mg: Baseline to Week 26		Canagliflozin 300 mg: Baseline to Week 26		Placebo/Sitagliptin: 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	31/115 (27%)		35/113 (31%)		40/114 (35.1%)		49/115 (42.6%)		48/113 (42.5%)		57/114 (50%)
Gastrointestinal disorders
Diarrhoea	6/115 (5.2%)		4/113 (3.5%)		4/114 (3.5%)		7/115 (6.1%)		7/113 (6.2%)		6/114 (5.3%)
General disorders
Oedema peripheral	2/115 (1.7%)		2/113 (1.8%)		4/114 (3.5%)		4/115 (3.5%)		2/113 (1.8%)		6/114 (5.3%)
Infections and infestations
Nasopharyngitis	6/115 (5.2%)		6/113 (5.3%)		11/114 (9.6%)		13/115 (11.3%)		11/113 (9.7%)		15/114 (13.2%)
Upper respiratory tract infection	7/115 (6.1%)		9/113 (8%)		5/114 (4.4%)		9/115 (7.8%)		14/113 (12.4%)		8/114 (7%)
Urinary tract infection	6/115 (5.2%)		4/113 (3.5%)		4/114 (3.5%)		9/115 (7.8%)		5/113 (4.4%)		9/114 (7.9%)
Vulvovaginal mycotic infection	0/115 (0%)		3/113 (2.7%)		6/114 (5.3%)		1/115 (0.9%)		3/113 (2.7%)		6/114 (5.3%)
Metabolism and nutrition disorders
Hypoglycaemia	2/115 (1.7%)		1/113 (0.9%)		6/114 (5.3%)		3/115 (2.6%)		3/113 (2.7%)		5/114 (4.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/115 (1.7%)		1/113 (0.9%)		6/114 (5.3%)		3/115 (2.6%)		3/113 (2.7%)		9/114 (7.9%)
Back pain	3/115 (2.6%)		8/113 (7.1%)		5/114 (4.4%)		4/115 (3.5%)		10/113 (8.8%)		7/114 (6.1%)
Muscle spasms	3/115 (2.6%)		1/113 (0.9%)		3/114 (2.6%)		6/115 (5.2%)		2/113 (1.8%)		4/114 (3.5%)
Nervous system disorders
Headache	4/115 (3.5%)		3/113 (2.7%)		5/114 (4.4%)		5/115 (4.3%)		3/113 (2.7%)		6/114 (5.3%)
Renal and urinary disorders
Pollakiuria	1/115 (0.9%)		5/113 (4.4%)		7/114 (6.1%)		1/115 (0.9%)		6/113 (5.3%)		8/114 (7%)
Respiratory, thoracic and mediastinal disorders
Cough	6/115 (5.2%)		3/113 (2.7%)		1/114 (0.9%)		7/115 (6.1%)		5/113 (4.4%)		2/114 (1.8%)

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.