A 52-week International, Multicenter Trial With a Long -Term Extension to Evaluate Saxagliptin With Dapagliflozin in Combination With Metformin Compared to Glimepiride in Combination With Metformin in Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin Alone

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02419612
• Collaborator: (none)
• Enrollment: 444
• Locations: 84
• Arms: 2
• Actual Duration (Months): 49.1
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This clincial trial is evaluating if the co-administration of saxagliptin and dapagliflozin, in addition to metformin, results in better glycemic control, as measured by HbA1c, over a treatment period of 52 weeks, compared to the addition of glimepiride to metformin in subjects with Type 2 Diabetes Mellitus who have inadequate glycemic control on Metformin Alone. We will compare the change from baseline in HbA1c achieved with saxagliptin, in co-administration with dapagliflozin, added to current background therapy with metformin compared to glimepiride added to current background therapy with metformin ≥1500 mg at Week 52.

Condition or Disease	Intervention/Treatment	Phase
Diabetes	Drug: Saxagliptin; Drug: Dapagliflozin; Drug: Glimepiride; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 444 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A 52-week International, Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel Group, Phase 3bTrial With a Blinded 104-week Long -Term Extension Period to Evaluate the Efficacy and Safety of Saxagliptin Co-administered With Dapagliflozin in Combination With Metformin Compared to Glimepiride in Combination With Metformin ≥1500 mg in Adult Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin Therapy Alone
• Actual Study Start Date: Aug 14, 2015
• Actual Primary Completion Date: Aug 29, 2017
• Actual Study Completion Date: Sep 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Saxagliptin 5 mg/ dapagliflozin 10mg or Placebo Saxagliptin 5 mg /dapagliflozin 10 mg Placebo once a day orally	Drug: Saxagliptin; Drug: Dapagliflozin; Other: Placebo
Experimental: Glimepiride or Placebo Glimepiride or placebo 1mg or 2mg or 3mg or 4mg or 6mg once a day orally	Drug: Glimepiride; Other: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1c (HbA1c) at Week 52 [Baseline and Week 52]

   To examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.

Secondary Outcome Measures

1. Change From Baseline in Total Body Weight at Week 52 [Baseline and Week 52]

   To examine whether the mean change from baseline in total body weight with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.

2. Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 52 [At Week 52]

   Therapeutic glycemic response was defined as HbA1c <7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 52 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c.

3. Change From Baseline in Systolic Blood Pressure (SBP) at Week 52 [Baseline and Week 52]

   To examine whether the change from baseline in SBP with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.

4. Percentage of Subjects With Treatment Intensification During the 52-week Short-term Treatment Period [Up to Week 52]

   Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after the 52-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 52 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 52-week short -term treatment period.

5. Percentage of Subjects With Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. [Up to Week 156]

   Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 156-week treatment period.

6. Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 156 [At Week 156]

   Therapeutic glycemic response was defined as HbA1c <7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 156 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c.

7. Time to Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. [Up to Week 156]

   Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. Time to treatment intensification curves were generated using Kaplan-Meier estimates and compared using a Cox proportional hazards model.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Subjects must be willing and able to give signed and dated written informed consent

• Patients with Type 2 diabetes mellitus (T2DM) with inadequate glycemic control

• Subjects should have been taking the same daily dose of metformin ≥ 1500 mg

• Fasting Plasma Glucose ≤ 270 mg/dL (≤15 mmol/L)

• Males and females, aged ≥18 years old at time of screening visit

• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test

• WOCBP and males must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug

Exclusion Criteria:

• Clinical diagnosis of type I diabetes

• History of diabetic ketoacidosis

• Cardiovascular/vascular diseases within 3 months of the enrollment

• Renal disease

• Hepatic diseases

• History of, or currently, acute or chronic pancreatitis

• Hematological and oncological disease/conditions

• Patients who have contraindications to therapy being studied

• Patients on weight loss program(s)

• Replacement or chronic systemic corticosteroid therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35211
2	Research Site	Chandler	Arizona	United States	85224
3	Research Site	Tempe	Arizona	United States	85283
4	Research Site	Huntington Park	California	United States	90255
5	Research Site	Los Angeles	California	United States	90057
6	Research Site	Sacramento	California	United States	95823
7	Research Site	Tarzana	California	United States	91356
8	Research Site	Waterbury	Connecticut	United States	06708
9	Research Site	Jacksonville	Florida	United States	32207
10	Research Site	Jacksonville	Florida	United States	32277
11	Research Site	Kissimmee	Florida	United States	34744
12	Research Site	Miami	Florida	United States	33126
13	Research Site	Miami	Florida	United States	33174
14	Research Site	New Port Richey	Florida	United States	34652
15	Research Site	Palm Harbor	Florida	United States	34684
16	Research Site	Edina	Minnesota	United States	55435
17	Research Site	Las Vegas	Nevada	United States	89128
18	Research Site	Greer	South Carolina	United States	29651
19	Research Site	Bristol	Tennessee	United States	37620
20	Research Site	Knoxville	Tennessee	United States	37912
21	Research Site	Dallas	Texas	United States	75230
22	Research Site	San Antonio	Texas	United States	78229
23	Research Site	Cheb		Czechia	350 02
24	Research Site	Hradec Kralove		Czechia	503 41
25	Research Site	Krnov		Czechia	794 01
26	Research Site	Kromeriz		Czechia	767 01
27	Research Site	Nachod		Czechia	54701
28	Research Site	Praha 4		Czechia	140 00
29	Research Site	Praha 4		Czechia	149 00
30	Research Site	Dresden		Germany	01307
31	Research Site	Leipzig		Germany	04249
32	Research Site	Ajka		Hungary	8400
33	Research Site	Balatonfüred		Hungary	8230
34	Research Site	Budapest		Hungary	1033
35	Research Site	Budapest		Hungary	1089
36	Research Site	Budapest		Hungary
37	Research Site	Debrecen		Hungary	4032
38	Research Site	Eger		Hungary	3300
39	Research Site	Gyula		Hungary	5700
40	Research Site	Kaposvár		Hungary	7400
41	Research Site	Kecskemét		Hungary	6000
42	Research Site	Nyíregyháza		Hungary	4405
43	Research Site	Zalaegerszeg		Hungary	8900
44	Research Site	Aguascalientes		Mexico	20230
45	Research Site	Chihuahua		Mexico	31237
46	Research Site	Cuautla		Mexico	62746
47	Research Site	Guadalajara		Mexico	44600
48	Research Site	Guanajuato		Mexico	38000
49	Research Site	Monterrey		Mexico	64460
50	Research Site	Veracruz		Mexico	91910
51	Research Site	Białystok		Poland	15-351
52	Research Site	Katowice		Poland	40-648
53	Research Site	Kraków		Poland	31-156
54	Research Site	Kraków		Poland	31-261
55	Research Site	Opole		Poland	45-367
56	Research Site	Oswiecim		Poland	32-600
57	Research Site	Poznań		Poland	61-655
58	Research Site	Warszawa		Poland	00-465
59	Research Site	Warszawa		Poland	02-507
60	Research Site	Wroclaw		Poland	50-349
61	Research Site	Łódź		Poland	90-242
62	Research Site	Brasov		Romania	500269
63	Research Site	Bucuresti		Romania	020045
64	Research Site	Bucuresti		Romania	020359
65	Research Site	Buzau		Romania	120203
66	Research Site	Galati		Romania	800291
67	Research Site	Oradea		Romania	410032
68	Research Site	Oradea		Romania	410169
69	Research Site	Ploiesti		Romania	100163
70	Research Site	Ploiesti		Romania	100342
71	Research Site	Satu-Mare		Romania	440055
72	Research Site	Targu		Romania	540142
73	Research Site	Timisoara		Romania	300736
74	Research Site	Novosibirsk		Russian Federation	630087
75	Research Site	Saint Petersburg		Russian Federation	195257
76	Research Site	Smolensk		Russian Federation	214018
77	Research Site	St. Petersburg		Russian Federation	190013
78	Research Site	St. Petersburg		Russian Federation	194354
79	Research Site	St. Petersburg		Russian Federation	196084
80	Research Site	St.-Petersburg		Russian Federation	195176
81	Research Site	Göteborg		Sweden	413 45
82	Research Site	Helsingborg		Sweden	25220
83	Research Site	Rättvik		Sweden	79530
84	Research Site	Dundee		United Kingdom	DD1 9SY

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 8, 2018
• Statistical Analysis Plan - Oct 8, 2019

More Information

Additional Information:

• CV181365_CSP_redacted

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02419612
• Other Study ID Numbers: CV181-365
• First Posted: Apr 17, 2015
• Last Update Posted: Jun 23, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Diabetes Mellitus; Dapagliflozin; Glimepiride; Saxagliptin

Study Results

Participant Flow

Recruitment Details	A total of 444 subjects were randomized in this international, multi-center study which was conducted at 88 centers in 10 countries between 14 Aug 2015 and 18 September 2019.
Pre-assignment Detail	The study duration was up to 160 weeks, consisting of a 2-week screening period, 2-week lead-in period, 52-week short-term treatment period, and 104-week long-term treatment period (156-week treatment period). One subject did not start the short-term treatment period and so only 443 subjects received treatment.

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
Period Title: Short-term Treatment Period
STARTED	227	217
Recevied Treatment	227	216
COMPLETED	210	194
NOT COMPLETED	17	23
Period Title: Short-term Treatment Period
STARTED	196	186
Received Treatment	196	183
COMPLETED	174	164
NOT COMPLETED	22	22

Baseline Characteristics

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride	Total
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.	Total of all reporting groups
Overall Participants	227	216	443
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.1 (10.11)	56.1 (9.23)	56.1 (9.68)
Sex: Female, Male (Count of Participants)
Female	110 48.5%	115 53.2%	225 50.8%
Male	117 51.5%	101 46.8%	218 49.2%
Race/Ethnicity, Customized (Count of Participants)
American Indian Or Alaska Native	11 4.8%	10 4.6%	21 4.7%
Black Or African American	4 1.8%	5 2.3%	9 2%
Native Hawaiian Or Other Pacific Islander	0 0%	1 0.5%	1 0.2%
Other	6 2.6%	4 1.9%	10 2.3%
White	206 90.7%	196 90.7%	402 90.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1c (HbA1c) at Week 52
Description	To examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period. Of these, only subjects with an evaluable baseline measurement for a given endpoint were analysed.

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
Measure Participants	218	212
Least Squares Mean (95% Confidence Interval) [% HbA1c]	-1.35	-0.98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg and Saxagliptin 5mg, Titrated Glimepiride
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted for for treatment, baseline HbA1c, visit, treatment-by-visit interaction, and baseline HbA1c-by-visit interaction.
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.57 to -0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.099
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Total Body Weight at Week 52
Description	To examine whether the mean change from baseline in total body weight with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period. Of these, only subjects with an evaluable baseline measurement for a given endpoint were analysed.

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
Measure Participants	224	214
Least Squares Mean (95% Confidence Interval) [kilogram (kg)]	-3.11	0.95

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg and Saxagliptin 5mg, Titrated Glimepiride
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted for for treatment, baseline body weight, visit, treatment-by-visit interaction, and baseline body weight-by-visit interaction.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.06
	Confidence Interval	(2-Sided) 95%; -4.84 to -3.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.397
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 52
Description	Therapeutic glycemic response was defined as HbA1c <7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 52 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c.
Time Frame	At Week 52

Outcome Measure Data

Analysis Population Description

The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
Measure Participants	227	216
Number (95% Confidence Interval) [Percentage of subjects]	44.3	34.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg and Saxagliptin 5mg, Titrated Glimepiride
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments
	Method	Regression, Logistic
	Comments	Adjusted for baseline HbA1c value
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.5
	Confidence Interval	() 95%; 1.01 to 2.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP) at Week 52
Description	To examine whether the change from baseline in SBP with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period. Of these, only subjects with an evaluable baseline measurement for a given endpoint were analysed.

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
Measure Participants	224	214
Least Squares Mean (95% Confidence Interval) [mmHg]	-2.6	1.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg and Saxagliptin 5mg, Titrated Glimepiride
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted for treatment, baseline SBP, visit, treatment-by-visit interaction, and baseline SBP-by-visit interaction
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.6
	Confidence Interval	(2-Sided) 95%; -6.3 to -1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.35
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Subjects With Treatment Intensification During the 52-week Short-term Treatment Period
Description	Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after the 52-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 52 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 52-week short -term treatment period.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
Measure Participants	227	216
Number [Percentage of Subjects]	1.3	8.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg and Saxagliptin 5mg, Titrated Glimepiride
	Comments	Time to treatment intensification was analyzed using a Cox proportional hazards model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	This endpoint did not meet the required number of events (n=10) in each treatment arm, hence was excluded from sequential testing.
	Method	Regression, Cox Proportional Hazards
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; 0.04 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Subjects With Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period.
Description	Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 156-week treatment period.
Time Frame	Up to Week 156

Outcome Measure Data

Analysis Population Description

The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
Measure Participants	227	216
Number [Percentage of Subjects]	37.0	55.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg and Saxagliptin 5mg, Titrated Glimepiride
	Comments	Time to treatment intensification was analyzed using a Cox proportional hazards model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox Proportional Hazards
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 156
Description	Therapeutic glycemic response was defined as HbA1c <7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 156 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c.
Time Frame	At Week 156

Outcome Measure Data

Analysis Population Description

The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
Measure Participants	227	216
Number (95% Confidence Interval) [Percentage of Subjects]	21.4	11.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg and Saxagliptin 5mg, Titrated Glimepiride
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Regression, Logistic
	Comments	Adjusted for baseline HbA1c value.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; 1.23 to 3.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.54
	Estimation Comments

8. Secondary Outcome

Title	Time to Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period.
Description	Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. Time to treatment intensification curves were generated using Kaplan-Meier estimates and compared using a Cox proportional hazards model.
Time Frame	Up to Week 156

Outcome Measure Data

Analysis Population Description

The randomized subject data set included all randomized subjects who received at least 1 dose of study medication during the double-blind treatment period.

Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg	Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day	Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
Measure Participants	227	216
Median (95% Confidence Interval) [Weeks]	NA	92.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg and Saxagliptin 5mg, Titrated Glimepiride
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox Proportional Hazards
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All adverse events (AEs), including serious adverse events (SAEs), were collected on or after the date of first dose of short-term study medication and up to and including 4 days (other AEs) or 30 days (SAEs) after last dose. Up to a total of 160 weeks.
Adverse Event Reporting Description	The treated subjects data set for the short-tem plus long-term treatment period consisted of all subjects who received at least 1 dose of double-blind study medication during the short-term double-blind treatment period.
Arm/Group Title	Dapagliflozin 10mg and Saxagliptin 5mg		Titrated Glimepiride
Arm/Group Description	Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day		Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
All Cause Mortality
	Dapagliflozin 10mg and Saxagliptin 5mg		Titrated Glimepiride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/227 (0.4%)		3/216 (1.4%)
Serious Adverse Events
	Dapagliflozin 10mg and Saxagliptin 5mg		Titrated Glimepiride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/227 (12.8%)		24/216 (11.1%)
Cardiac disorders
Coronary artery stenosis	1/227 (0.4%)	1	0/216 (0%)	0
Acute myocardial infarction	0/227 (0%)	0	1/216 (0.5%)	1
Angina pectoris	0/227 (0%)	0	1/216 (0.5%)	1
Cardiac failure chronic	0/227 (0%)	0	1/216 (0.5%)	1
Cardiac failure congestive	0/227 (0%)	0	1/216 (0.5%)	1
Ear and labyrinth disorders
Vertigo positional	0/227 (0%)	0	1/216 (0.5%)	1
Endocrine disorders
Thyroid mass	1/227 (0.4%)	1	0/216 (0%)	0
Gastrointestinal disorders
Obstructive pancreatitis	0/227 (0%)	0	1/216 (0.5%)	1
General disorders
Non-cardiac chest pain	0/227 (0%)	0	1/216 (0.5%)	1
Infections and infestations
Cellulitis	0/227 (0%)	0	1/216 (0.5%)	1
Gangrene	1/227 (0.4%)	1	0/216 (0%)	0
Laryngitis	1/227 (0.4%)	1	0/216 (0%)	0
Pneumonia	1/227 (0.4%)	1	2/216 (0.9%)	2
Sepsis	1/227 (0.4%)	1	0/216 (0%)	0
Sinusitis	0/227 (0%)	0	1/216 (0.5%)	1
Urinary tract infection	1/227 (0.4%)	3	0/216 (0%)	0
Abdominal wall infection	0/227 (0%)	0	1/216 (0.5%)	1
Erysipelas	0/227 (0%)	0	1/216 (0.5%)	1
Injury, poisoning and procedural complications
Overdose	1/227 (0.4%)	1	1/216 (0.5%)	1
Road traffic accident	0/227 (0%)	0	1/216 (0.5%)	1
Limb traumatic amputation	1/227 (0.4%)	1	0/216 (0%)	0
Tibia fracture	1/227 (0.4%)	1	0/216 (0%)	0
Humerus fracture	1/227 (0.4%)	1	0/216 (0%)	0
Investigations
Hormone level abnormal	1/227 (0.4%)	1	0/216 (0%)	0
Metabolism and nutrition disorders
Hypoglycaemia	1/227 (0.4%)	1	0/216 (0%)	0
Musculoskeletal and connective tissue disorders
Spinal osteoarthritis	0/227 (0%)	0	1/216 (0.5%)	1
Back pain	0/227 (0%)	0	1/216 (0.5%)	1
Periarthritis	1/227 (0.4%)	1	0/216 (0%)	0
Arthralgia	1/227 (0.4%)	1	0/216 (0%)	0
Osteoarthritis	2/227 (0.9%)	2	0/216 (0%)	0
Intervertebral disc protrusion	2/227 (0.9%)	2	0/216 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colorectal cancer	1/227 (0.4%)	1	0/216 (0%)	0
Endometrial adenocarcinoma	1/227 (0.4%)	1	2/216 (0.9%)	2
Pituitary tumour benign	1/227 (0.4%)	1	0/216 (0%)	0
Adenocarcinoma gastric	0/227 (0%)	0	1/216 (0.5%)	1
Bladder cancer	0/227 (0%)	0	1/216 (0.5%)	1
Oesophageal adenocarcinoma	0/227 (0%)	0	1/216 (0.5%)	1
Squamous cell carcinoma of lung	0/227 (0%)	0	1/216 (0.5%)	1
Nervous system disorders
Cerebrovascular accident	1/227 (0.4%)	1	0/216 (0%)	0
Chronic inflammatory demyelinating polyradiculoneuropathy	1/227 (0.4%)	1	0/216 (0%)	0
Generalised tonic-clonic seizure	1/227 (0.4%)	1	0/216 (0%)	0
Guillain-Barre syndrome	1/227 (0.4%)	1	0/216 (0%)	0
Ischaemic stroke	0/227 (0%)	0	2/216 (0.9%)	3
Vertebrobasilar insufficiency	2/227 (0.9%)	2	0/216 (0%)	0
Carotid artery occlusion	0/227 (0%)	0	1/216 (0.5%)	1
Cerebral infarction	0/227 (0%)	0	1/216 (0.5%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	2/227 (0.9%)	2	0/216 (0%)	0
Reproductive system and breast disorders
Uterine haemorrhage	0/227 (0%)	0	1/216 (0.5%)	1
Vascular disorders
Aortic stenosis	0/227 (0%)	0	1/216 (0.5%)	1
Hypertensive crisis	1/227 (0.4%)	1	0/216 (0%)	0
Peripheral ischaemia	1/227 (0.4%)	1	1/216 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Dapagliflozin 10mg and Saxagliptin 5mg		Titrated Glimepiride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	99/227 (43.6%)		106/216 (49.1%)
Gastrointestinal disorders
Diarrhoea	10/227 (4.4%)	11	12/216 (5.6%)	13
Infections and infestations
Upper respiratory tract infection	23/227 (10.1%)	29	21/216 (9.7%)	27
Bronchitis	11/227 (4.8%)	15	17/216 (7.9%)	21
Influenza	9/227 (4%)	10	12/216 (5.6%)	16
Nasopharyngitis	14/227 (6.2%)	20	19/216 (8.8%)	25
Pharyngitis	6/227 (2.6%)	9	12/216 (5.6%)	13
Urinary tract infection	31/227 (13.7%)	41	21/216 (9.7%)	28
Metabolism and nutrition disorders
Dyslipidaemia	2/227 (0.9%)	2	13/216 (6%)	14
Musculoskeletal and connective tissue disorders
Back pain	12/227 (5.3%)	16	7/216 (3.2%)	8
Nervous system disorders
Headache	18/227 (7.9%)	21	16/216 (7.4%)	20
Vascular disorders
Hypertension	7/227 (3.1%)	7	18/216 (8.3%)	18

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.