A Study to Evaluate the Efficacy and Safety of the Addition of Canagliflozin in Participants With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin and Sitagliptin

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02025907
• Collaborator: (none)
• Enrollment: 218
• Locations: 57
• Arms: 2
• Duration (Months): 19
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the effect of canagliflozin (JNJ-28431754) compared to placebo in the treatment of participants with Type 2 Diabetes Mellitus (T2DM), who have inadequate glycemic control on maximally or near-maximally effective doses of metformin and sitagliptin.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Canagliflozin, 100 mg; Drug: Canagliflozin, 300 mg; Drug: Placebo	Phase 4

Detailed Description

This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor participant knows the identity of the assigned treatment), placebo-controlled (an inactive substance that is compared with a study drug, to test whether the study drug has a real effect), multicenter study of efficacy, safety, and tolerability of canagliflozin in participants with T2DM, who have inadequate glycemic (blood sugar) control on maximally or near-maximally effective doses of metformin >=1500 mg/day and sitagliptin 100 mg/day. Approximately 200 participants will be randomly assigned to 1 of 2 treatment groups in 1:1 ratio for 26 weeks. During the study the participants will be also provided with diet and exercise counseling (standardized non-pharmacological therapy).

Study Design

• Study Type: Interventional
• Actual Enrollment: 218 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, 2-arm, Parallel-group, 26-week, 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 Sitagliptin Therapy
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Canagliflozin (JNJ-28431754) Each participant will receive canagliflozin (JNJ-28431754) 100 mg once daily during the first 6 weeks, then the dose may be increased to 300 mg once daily.	Drug: Canagliflozin, 100 mg; One 100 mg capsule taken orally (by mouth) once daily.; Drug: Canagliflozin, 300 mg; One 300 mg capsule taken orally (by mouth) once daily.
Placebo Comparator: Placebo Each participant will receive placebo (inactive medication) once daily for 28 weeks.	Drug: Placebo; One placebo capsule taken orally (by mouth) once daily.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26 [Baseline and Week 26]

Secondary Outcome Measures

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

2. Percent Change From Baseline in Body Weight at Week 26 [Baseline and Week 26]

3. Percentage of Participants With HbA1c Less Than (<) 7.0 Percent at Week 26 [Week 26]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must have a diagnosis of type 2 diabetes mellitus

• Must have a screening HbA1c of >=7.5% to <=10.5%

• Must be on metformin >=1500 mg/day and sitagliptin 100 mg/day (or equivalent fixed dose combination) at a stable dose for at least 12 weeks before screening

Exclusion Criteria:

• History of diabetic ketoacidosis or T1DM, hereditary glucose-galactose malabsorption or primary renal glycosuria

• A myocardial infarction, unstable angina, revascularization procedure or cerebrovascular accident within 12 weeks before screening

• eGFR <60 ml/min/1.73m2, or serum creatinine >=1.4 mg/dL for men and >=1.3 mg/dL for women

• Known significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis)

• Major surgery (ie, requiring general anesthesia) within 12 weeks before screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Montgomery	Alabama	United States
2		Phoenix	Arizona	United States
3		Little Rock	Arkansas	United States
4		Northridge	California	United States
5		Norwalk	California	United States
6		Rancho Cucamonga	California	United States
7		San Ramon	California	United States
8		Aurora	Colorado	United States
9		Denver	Colorado	United States
10		Littleton	Colorado	United States
11		Cooper City	Florida	United States
12		Miami	Florida	United States
13		North Miami Beach	Florida	United States
14		Atlanta	Georgia	United States
15		Perry	Georgia	United States
16		Shawnee Mission	Kansas	United States
17		Marrero	Louisiana	United States
18		Metairie	Louisiana	United States
19		Metarie	Louisiana	United States
20		Rockville	Maryland	United States
21		Jackson	Mississippi	United States
22		Picayune	Mississippi	United States
23		Saint Louis	Missouri	United States
24		Nashua	New Hampshire	United States
25		Albuquerque	New Mexico	United States
26		Albany	New York	United States
27		Arlington	Texas	United States
28		San Antonio	Texas	United States
29		Sugarland	Texas	United States
30		Bountiful	Utah	United States
31		Coffs Harbour		Australia
32		Freemantle		Australia
33		Geelong		Australia
34		Heidelberg		Australia
35		Herston		Australia
36		Melbourne		Australia
37		Merewether		Australia
38		Sherwood		Australia
39		Sydney		Australia
40		Wollongong		Australia
41		Brampton	Ontario	Canada
42		Hawkesbury	Ontario	Canada
43		Toronto	Ontario	Canada
44		La Rochelle Cedex 1 Poitou-Cha		France
45		La Tronche		France
46		Nancy		France
47		Narbonne Cedex		France
48		Nice Cedex 3		France
49		Paris Cedex 15		France
50		Venissieux		France
51		Freiburg		Germany
52		Fulda		Germany
53		Hamburg		Germany
54		Münster		Germany
55		Neuwied		Germany
56		Pirna		Germany
57		Speyer		Germany

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: NCT02025907
• Other Study ID Numbers: CR103477; 2013-004819-40; 28431754DIA4004
• First Posted: Jan 1, 2014
• Last Update Posted: Oct 31, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by Janssen Research & Development, LLC: Diabetes Mellitus, Type 2; Canagliflozin; Hemoglobin A1c; Metformin; Sitagliptin; T2DM; JNJ-28431754
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Canagliflozin

Study Results

Participant Flow

Pre-assignment Detail	One participant was randomized at 2 different sites (once to placebo and once to canagliflozin) and was therefore counted twice in the total number of randomized participants. The participant was withdrawn from the study and not included in any efficacy or safety analyses.

Arm/Group Title	Placebo	Canagliflozin
Arm/Group Description	Participants administered with placebo (inactive medication) once daily for 26 weeks.	Participants administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.
Period Title: Overall Study
STARTED	108	108
COMPLETED	81	96
NOT COMPLETED	27	12

Baseline Characteristics

Arm/Group Title	Placebo	Canagliflozin	Total
Arm/Group Description	Participants administered with placebo (inactive medication) once daily for 26 weeks.	Participants administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.	Total of all reporting groups
Overall Participants	106	107	213
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.5 (10.14)	57.4 (9.28)	57.4 (9.69)
Gender (Count of Participants)
Female	51 48.1%	41 38.3%	92 43.2%
Male	55 51.9%	66 61.7%	121 56.8%
Region of Enrollment (participants) [Number]
Australia	13 12.3%	22 20.6%	35 16.4%
Canada	16 15.1%	23 21.5%	39 18.3%
France	10 9.4%	6 5.6%	16 7.5%
Germany	16 15.1%	13 12.1%	29 13.6%
United States	51 48.1%	43 40.2%	94 44.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

mITT population included all randomized participants who received at least 1 dose of double-blind study drug. A total of 3 participants were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Canagliflozin
Arm/Group Description	Participants administered with placebo (inactive medication) once daily for 26 weeks.	Participants administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.
Measure Participants	94	99
Least Squares Mean (Standard Error) [percentage of glycosylated hemoglobin]	-0.01 (0.119)	-0.91 (0.113)

2. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

mITT population included all randomized participants who received at least 1 dose of double-blind study drug. A total of 3 participants were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Canagliflozin
Arm/Group Description	Participants administered with placebo (inactive medication) once daily for 26 weeks.	Participants administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.
Measure Participants	104	103
Least Squares Mean (Standard Error) [millimoles per liter]	-0.14 (0.281)	-1.65 (0.264)

3. Secondary Outcome

Title	Percent Change From Baseline in Body Weight at Week 26
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

mITT population included all randomized participants who received at least 1 dose of double-blind study drug. A total of 3 participants were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Canagliflozin
Arm/Group Description	Participants administered with placebo (inactive medication) once daily for 26 weeks.	Participants administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.
Measure Participants	104	103
Least Squares Mean (Standard Error) [percent change]	-1.60 (0.337)	-3.35 (0.324)

4. Secondary Outcome

Title	Percentage of Participants With HbA1c Less Than (<) 7.0 Percent at Week 26
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

mITT population included all randomized participants who received at least 1 dose of double-blind study drug. A total of 3 participants were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Canagliflozin
Arm/Group Description	Participants administered with placebo (inactive medication) once daily for 26 weeks.	Participants administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.
Measure Participants	82	96
Number [percentage of participants]	12.2 11.5%	32.3 30.2%

5. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP) at Week 26
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

mITT population included all randomized participants who received at least 1 dose of double-blind study drug. A total of 3 participants were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Canagliflozin
Arm/Group Description	Participants administered with placebo (inactive medication) once daily for 26 weeks.	Participants administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.
Measure Participants	104	103
Least Squares Mean (Standard Error) [millimeter of mercury (mmHg)]	0.09 (1.123)	-5.76 (1.078)

Adverse Events

Time Frame	From Baseline, up to end of treatment (Approximately 31 weeks)
Adverse Event Reporting Description	Safety population included all randomized participants who received at least 1 dose of double-blind study drug and 3 participants who were excluded from the mITT population due to potential misconduct and GCP compliance issues.
Arm/Group Title	Placebo		Canagliflozin
Arm/Group Description	Participants administered with placebo (inactive medication) once daily for 26 weeks.		Participants administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.
All Cause Mortality
	Placebo		Canagliflozin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Canagliflozin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/108 (1.9%)		2/108 (1.9%)
Cardiac disorders
Angina Unstable	0/108 (0%)		1/108 (0.9%)
Infections and infestations
Diverticulitis	0/108 (0%)		1/108 (0.9%)
Nervous system disorders
Cerebral Infarction	1/108 (0.9%)		0/108 (0%)
Transient Ischaemic Attack	1/108 (0.9%)		0/108 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Canagliflozin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/108 (14.8%)		18/108 (16.7%)
Infections and infestations
Nasopharyngitis	6/108 (5.6%)		6/108 (5.6%)
Upper Respiratory Tract Infection	3/108 (2.8%)		2/108 (1.9%)
Metabolism and nutrition disorders
Hyperglycaemia	5/108 (4.6%)		0/108 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	1/108 (0.9%)		3/108 (2.8%)
Pain in Extremity	1/108 (0.9%)		3/108 (2.8%)
Psychiatric disorders
Depression	0/108 (0%)		3/108 (2.8%)
Renal and urinary disorders
Polyuria	3/108 (2.8%)		3/108 (2.8%)

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.