An Efficacy, Safety, and Tolerability Study of Canagliflozin in the Treatment of Patients With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Monotherapy

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01340664
• Collaborator: (none)
• Enrollment: 279
• Locations: 64
• Arms: 3
• Duration (Months): 9
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.5

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 monotherapy (ie, treatment with a single drug) and have inadequate glycemic (blood sugar) control.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Canagliflozin 50 mg; Drug: Placebo; Drug: Canagliflozin 150 mg; Drug: Metformin	Phase 2

Detailed Description

This is a randomized (study drug assigned by chance), double-blind (neither the patient nor the study doctor will know the identity of assigned study drug), placebo-controlled, parallel-group,3-arm (3 treatment groups) multicenter study to determine the efficacy, safety, and tolerability of canagliflozin compared to placebo (a capsule that is identical in appearance to canagliflozin but does not contain active drug) in patients with type 2 diabetes mellitus (T2DM) who are not achieving an adequate response from current antihyperglycemic therapy with metformin to control their diabetes. Canagliflozin (a Sodium-Glucose Cotransporter 2 inhibitor) is currently under development to lower blood sugar levels in patients with T2DM. Patients will take single-blind placebo capsules orally (by mouth) for 2 weeks before randomization. Patients will be randomly assigned canagliflozin or matching placebo, orally, twice daily, with 1 capsule taken with the morning meal and 1 capsule taken with the evening meal (2 capsules per day) and concurrent with metformin, if applicable, for up to 18 weeks. The dosing time of metformin should remain the same throughout the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 279 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, 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
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Canagliflozin 50 mg bid Each patient will receive 50 mg canagliflozin twice daily for 18 weeks.	Drug: Canagliflozin 50 mg; One canagliflozin 50-mg capsule taken orally twice daily with a meal for 18 weeks; Drug: Metformin; The patient's stable daily dose of Metformin background therapy should be continued throughout the study.
Experimental: Canagliflozin 150 mg bid Each patient will receive 150 mg canagliflozin twice daily for 18 weeks	Drug: Canagliflozin 150 mg; 1 canagliflozin 150-mg capsule taken orally twice daily with a meal for 18 weeks; Drug: Metformin; The patient's stable daily dose of Metformin background therapy should be continued throughout the study.
Placebo Comparator: Placebo Each patient will receive matching placebo twice daily for 18 weeks	Drug: Placebo; 1 placebo capsule taken orally twice daily with a meal for 18 weeks; Drug: Metformin; The patient's stable daily dose of Metformin background therapy should be continued throughout the study.

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c From Baseline to Week 18 [Day 1 (Baseline) and Week 18]

   The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 18 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. Change in Fasting Plasma Glucose (FPG) From Baseline to Week 18 [Day 1 (Baseline) and Week 18]

   The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 18 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.

2. Percent Change in Body Weight From Baseline to Week 18 [Day 1 (Baseline) and Week 18]

   The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 18 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.

3. Percentage of Patients With HbA1c <7% at Week 18 [Week 18]

   The table below shows the percentage of patients with HbA1c <7% at Week 18 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage.

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

• 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, 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		Little Rock	Arkansas	United States
2		National City	California	United States
3		Spring Valley	California	United States
4		Bradenton	Florida	United States
5		Marianna	Florida	United States
6		Savannah	Georgia	United States
7		Avon	Indiana	United States
8		Valparaiso	Indiana	United States
9		Madisonville	Kentucky	United States
10		Metairie	Louisiana	United States
11		Charlotte	North Carolina	United States
12		Columbus	Ohio	United States
13		Mason	Ohio	United States
14		Perrysburg	Ohio	United States
15		Tulsa	Oklahoma	United States
16		Yukon	Oklahoma	United States
17		Oregon City	Oregon	United States
18		Pittsburg	Pennsylvania	United States
19		East Providence	Rhode Island	United States
20		Nashville	Tennessee	United States
21		Houston	Texas	United States
22		Pearland	Texas	United States
23		San Antonio	Texas	United States
24		Bountiful	Utah	United States
25		Virginia Beach	Virginia	United States
26		Milwaukee	Wisconsin	United States
27		St. John'S	Newfoundland and Labrador	Canada
28		Halifax	Nova Scotia	Canada
29		Brampton	Ontario	Canada
30		Toronto	Ontario	Canada
31		Saskatoon	Saskatchewan	Canada
32		Beroun		Czech Republic
33		Olomouc 9		Czech Republic
34		Ostrava		Czech Republic
35		Pardubice		Czech Republic
36		Pisek		Czech Republic
37		Prague 10		Czech Republic
38		Praha 11		Czech Republic
39		Znojmo		Czech Republic
40		Aguascalientes		Mexico
41		Guadalajara, Jalisco.		Mexico
42		Monterrey		Mexico
43		Tampico		Mexico
44		Bacau		Romania
45		Brasov		Romania
46		Bucharest		Romania
47		Cluj-Napoca		Romania
48		Galati		Romania
49		Targu Mures		Romania
50		Kursk		Russian Federation
51		Moscow		Russian Federation
52		Saint-Petersburg		Russian Federation
53		Samara		Russian Federation
54		Saratov		Russian Federation
55		St Petersburg		Russian Federation
56		St-Petersburg		Russian Federation
57		Tyumen		Russian Federation
58		Voronezh		Russian Federation
59		Banska Bystrica		Slovakia
60		Bratislava		Slovakia
61		Kosice		Slovakia
62		Presov		Slovakia
63		Sahy		Slovakia
64		Trebisov		Slovakia

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC 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: NCT01340664
• Other Study ID Numbers: CR017914; 28431754DIA2003; 2010-024256-28
• First Posted: Apr 22, 2011
• Last Update Posted: Sep 16, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Janssen Research & Development, LLC: Canagliflozin; Placebo; Metformin; 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. The study was conducted between 27 June 2011 and 20 April 2012 and recruited patients from 60 study centers located in 7 countries worldwide.
Pre-assignment Detail	A total of 279 patients were randomly allocated to the 3 treatment arms in the study. All 279 patients received at least 1 dose of study drug and were included in the modified intent-to-treat analysis set which was used for the efficacy and safety analyses.

Arm/Group Title	Placebo	Canagliflozin 50 mg Bid	Canagliflozin 150 mg Bid
Arm/Group Description	Each patient received matching placebo twice daily for 18 weeks.	Each patient received 50 mg canagliflozin twice daily for 18 weeks.	Each patient received 150 mg canagliflozin twice daily for 18 weeks.
Period Title: Overall Study
STARTED	93	93	93
COMPLETED	86	85	80
NOT COMPLETED	7	8	13

Baseline Characteristics

Arm/Group Title	Placebo	Canagliflozin 50 mg Bid	Canagliflozin 150 mg Bid	Total
Arm/Group Description	Each patient received matching placebo twice daily for 18 weeks.	Each patient received 50 mg canagliflozin twice daily for 18 weeks.	Each patient received 150 mg canagliflozin twice daily for 18 weeks.	Total of all reporting groups
Overall Participants	93	93	93	279
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	79 84.9%	69 74.2%	75 80.6%	223 79.9%
>=65 years	14 15.1%	24 25.8%	18 19.4%	56 20.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (9.32)	58.6 (8.88)	56.7 (10.33)	57.4 (9.53)
Sex: Female, Male (Count of Participants)
Female	47 50.5%	53 57%	49 52.7%	149 53.4%
Male	46 49.5%	40 43%	44 47.3%	130 46.6%
Region Enroll (participants) [Number]
CANADA	17 18.3%	11 11.8%	12 12.9%	40 14.3%
CZECH REPUBLIC	2 2.2%	4 4.3%	6 6.5%	12 4.3%
MEXICO	10 10.8%	12 12.9%	10 10.8%	32 11.5%
ROMANIA	13 14%	15 16.1%	9 9.7%	37 13.3%
RUSSIAN FEDERATION	18 19.4%	17 18.3%	20 21.5%	55 19.7%
SLOVAKIA	10 10.8%	9 9.7%	11 11.8%	30 10.8%
UNITED STATES	23 24.7%	25 26.9%	25 26.9%	73 26.2%

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c From Baseline to Week 18
Description	The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 18 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 18

Outcome Measure Data

Analysis Population Description

This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when Week 18 values were missing. The table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 50 mg Bid	Canagliflozin 150 mg Bid
Arm/Group Description	Each patient received matching placebo twice daily for 18 weeks.	Each patient received 50 mg canagliflozin twice daily for 18 weeks	Each patient received 150 mg canagliflozin twice daily for 18 weeks
Measure Participants	92	90	91
Least Squares Mean (Standard Error) [Percent]	-0.01 (0.069)	-0.45 (0.070)	-0.61 (0.069)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 50 mg Bid
	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	-0.44
	Confidence Interval	(2-Sided) 95%; -0.637 to -0.251
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.098
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 150 mg Bid
	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	-0.60
	Confidence Interval	(2-Sided) 95%; -0.792 to -0.407
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.098
	Estimation Comments

2. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG) From Baseline to Week 18
Description	The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 18 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 18

Outcome Measure Data

Analysis Population Description

This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when Week 18 values were missing. The table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 50 mg Bid	Canagliflozin 150 mg Bid
Arm/Group Description	Each patient received matching placebo twice daily for 18 weeks.	Each patient received 50 mg canagliflozin twice daily for 18 weeks	Each patient received 150 mg canagliflozin twice daily for 18 weeks
Measure Participants	92	90	91
Least Squares Mean (Standard Error) [mg/dL]	8.1 (3.291)	-15.5 (3.327)	-15.9 (3.313)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 50 mg Bid
	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-Sqaures Mean Difference
	Estimated Value	-23.6
	Confidence Interval	(2-Sided) 95%; -32.78 to -14.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.673
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 150 mg Bid
	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-Sqaures Mean Difference
	Estimated Value	-24.0
	Confidence Interval	() 95%; -33.18 to -14.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.661
	Estimation Comments

3. Secondary Outcome

Title	Percent Change in Body Weight From Baseline to Week 18
Description	The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 18 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 18

Outcome Measure Data

Analysis Population Description

This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when Week 18 values were missing. The table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 50 mg Bid	Canagliflozin 150 mg Bid
Arm/Group Description	Each patient received matching placebo twice daily for 18 weeks.	Each patient received 50 mg canagliflozin twice daily for 18 weeks	Each patient received 150 mg canagliflozin twice daily for 18 weeks
Measure Participants	92	90	91
Least Squares Mean (Standard Error) [Percent change]	-0.6 (0.3)	-2.8 (0.3)	-3.2 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 50 mg Bid
	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	-2.2
	Confidence Interval	(2-Sided) 95%; -3.1 to -1.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.5
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 150 mg Bid
	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	-2.6
	Confidence Interval	(2-Sided) 95%; -3.5 to -1.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.5
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Patients With HbA1c <7% at Week 18
Description	The table below shows the percentage of patients with HbA1c <7% at Week 18 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage.
Time Frame	Week 18

Outcome Measure Data

Analysis Population Description

This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when Week 18 values were missing. The table includes only patients with both baseline and post baseline values.

Arm/Group Title	Placebo	Canagliflozin 50 mg Bid	Canagliflozin 150 mg Bid
Arm/Group Description	Each patient received matching placebo twice daily for 18 weeks.	Each patient received 50 mg canagliflozin twice daily for 18 weeks	Each patient received 150 mg canagliflozin twice daily for 18 weeks
Measure Participants	92	90	91
Number [Percentage of Participants]	31.5 33.9%	47.8 51.4%	57.1 61.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 50 mg Bid
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.43
	Confidence Interval	(2-Sided) 95%; 1.21 to 4.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Canagliflozin 150 mg Bid
	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	3.38
	Confidence Interval	(2-Sided) 95%; 1.68 to 6.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were reported for the duration of the study; each patient participated in the study for approximately 18 weeks.
Adverse Event Reporting Description	Only patients who had at least one of the treatment-emergent adverse events listed in the "Other (non-Serious) Adverse Event" table are included in the total number of patients with non-serious adverse Events.
Arm/Group Title	Placebo		Canagliflozin 50 mg Bid		Canagliflozin 150 mg Bid
Arm/Group Description	Each patient received matching placebo twice daily for 18 weeks		Each patient received 50 mg canagliflozin twice daily for 18 weeks.		Each patient received 150 mg canagliflozin twice daily for 18 weeks
All Cause Mortality
	Placebo		Canagliflozin 50 mg Bid		Canagliflozin 150 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Canagliflozin 50 mg Bid		Canagliflozin 150 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/93 (1.1%)		0/93 (0%)		3/93 (3.2%)
Gastrointestinal disorders
Oroantral fistula	0/93 (0%)		0/93 (0%)		1/93 (1.1%)
Infections and infestations
Pyelonephritis	0/93 (0%)		0/93 (0%)		1/93 (1.1%)
Injury, poisoning and procedural complications
Postoperative wound complication	0/93 (0%)		0/93 (0%)		1/93 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	0/93 (0%)		0/93 (0%)		1/93 (1.1%)
Renal and urinary disorders
Nephrolithiasis	0/93 (0%)		0/93 (0%)		1/93 (1.1%)
Reproductive system and breast disorders
Dysfunctional uterine bleeding	1/93 (1.1%)		0/93 (0%)		0/93 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Canagliflozin 50 mg Bid		Canagliflozin 150 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/93 (0%)		0/93 (0%)		0/93 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If an investigator wishes to publish information from 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. Expedited reviews will be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days to allow for filing of a patent application.