Efficacy and Safety of Dapagliflozin and Dapagliflozin Plus Saxagliptin in Combination With Metformin in Type 2 Diabetes Patients Compared With Sulphonylurea

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02471404
• Collaborator: (none)
• Enrollment: 939
• Locations: 173
• Arms: 3
• Actual Duration (Months): 17.7
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study is being carried out to see if dapagliflozin and dapagliflozin plus saxagliptin as an addition to metformin is effective and safe in treating patients with type 2 diabetes when compared to glimepiride (sulphonylurea) as an addition to metformin treatment.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus; Inadequate Glycaemic Control	Drug: Dapagliflozin; Drug: Saxagliptin; Drug: Glimepiride; Drug: Placebo for dapagliflozin; Drug: Placebo for saxagliptin; Drug: Placebo for glimepiride	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 939 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A 52-Week, Multi-Centre, Randomised, Parallel-Group, Double-Blind, Active Controlled, Phase IV Study to Evaluate the Safety and Efficacy of Dapagliflozin or Dapagliflozin Plus Saxagliptin Compared With Sulphonylurea All Given as Add-on Therapy to Metformin in Adult Patients With Type 2 Diabetes Who Have Inadequate Glycaemic Control on Metformin Monotherapy
• Actual Study Start Date: Sep 21, 2015
• Actual Primary Completion Date: Mar 13, 2017
• Actual Study Completion Date: Mar 13, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Dapagliflozin+metformin Dapagliflozin + saxagliptin placebo + glimepiride placebo + metformin	Drug: Dapagliflozin; 10 mg, orally Green, plain, diamond-shaped, film-coated tablet; Other Names: Forxiga ; Drug: Placebo for saxagliptin; Does not contain active ingredient, orally Plain, yellow, biconvex, round, film-coated tablet; Drug: Placebo for glimepiride; Does not contain active ingredient, orally. Opaque gray capsule
Active Comparator: Dapagliflozin+saxagliptin+metformin Dapagliflozin + saxagliptin + glimepiride placebo+ metformin	Drug: Dapagliflozin; 10 mg, orally Green, plain, diamond-shaped, film-coated tablet; Other Names: Forxiga ; Drug: Saxagliptin; 5 mg, orally Plain, yellow, biconvex, round, film-coated tablet; Other Names: Onglyza™ ; Drug: Placebo for glimepiride; Does not contain active ingredient, orally. Opaque gray capsule
Active Comparator: Glimepiride+metformin Glimepiride + dapagliflozin placebo + saxagliptin placebo + metformin	Drug: Glimepiride; 1, 2, or 4 mg, orally Opaque gray capsule; Other Names: Amaryl ; Drug: Placebo for dapagliflozin; Does not contain active ingredient, orally Green, plain, diamond-shaped, film-coated tablet; Drug: Placebo for saxagliptin; Does not contain active ingredient, orally Plain, yellow, biconvex, round, film-coated tablet

Outcome Measures

Primary Outcome Measures

1. Change in Haemoglobin A1c (HbA1c) From Baseline to Week 52 [Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis]

   Change in HbA1c from baseline (week 0) to week 52.

Secondary Outcome Measures

1. Patients With at Least One Episode of Confirmed Hypoglycaemia [Up to Week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis]

   Percentage of patients reporting at least 1 episode of hypoglycaemia (symptomatic + blood glucose <=50 mg/dL) during the double-blind treatment period

2. Change in Total Body Weight From Baseline at Week 52 [Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis]

   Change in body weight from baseline (week 0) to week 52

3. Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52 [Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis]

   Change in FPG from baseline (week 0) to week 52

4. Time to Rescue [Over the 52 week treatment period]

   The time to rescue (from first dose date after randomisation to start of rescue medication or discontinuation due to lack of glycaemic control) during the 52 week double blind treatment period

5. Number of Patients Rescued [Over the 52 week treatment period]

   Number (%) of patients rescued.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: Main Inclusion Criteria:

1. Is male or female and ≥18 and <75 years old at time of informed consent.

2. Has a HbA1c of ≥7.5% and ≤10.5% based on central laboratory results from Visit 1, with individual need for therapy escalation.

3. Currently treated with a stable maximum tolarated dose (MTD) (≥1500 mg/day) of metformin therapy for at least 8 weeks prior to Enrolment visit.

4. Has a BMI of ≤45 kg/m2 at Enrolment visit.

5. Has a C-peptide laboratory value of ≥1.0 ng/mL (0.33 nmol/L; 333.3 pmol/L) based on central laboratory results from Visit 1.

Main, Exclusion Criteria:

1. Clinically diagnosed with Type I diabetes, known diagnosis of maturity onset diabetes of the young (MODY), or secondary diabetes mellitus or known presence of glutamate decarboxylase 65 (GAD65) antibodies.

2. Patients who, in the judgment of the Investigator, may be at risk for dehydration or volume depletion that may affect the patient's safety and/or the interpretation of efficacy or safety data.

3. Clinically significant cardiovascular disease or procedure within 3 months prior to Enrolment or expected to require coronary revascularization procedure during the course of the study.

4. Concomitant treatment with loop diuretics

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Hodonin		Czechia	695 01
2	Research Site	Hradec Kralove		Czechia	500 05
3	Research Site	Jilove u Prahy		Czechia	254 01
4	Research Site	Ostrava - Belsky les		Czechia	700 30
5	Research Site	Pardubice		Czechia	530 02
6	Research Site	Plzen - Severni Predmesti		Czechia	301 00
7	Research Site	Praha - Klanovice		Czechia	190 14
8	Research Site	Prelouc		Czechia	535 01
9	Research Site	Uherske Hradiste		Czechia	686 01
10	Research Site	Zlin		Czechia	760 01
11	Research Site	Aschaffenburg		Germany	63739
12	Research Site	Bad Homburg		Germany	61348
13	Research Site	Bad Mergentheim		Germany	97980
14	Research Site	Bad Nauheim		Germany	61231
15	Research Site	Bad Neuenahr-Ahrweiler		Germany	53474
16	Research Site	Bad Oeynhausen		Germany	32545
17	Research Site	Bad Reichenhall		Germany	83435
18	Research Site	Berlin		Germany	10115
19	Research Site	Berlin		Germany	10409
20	Research Site	Berlin		Germany	10629
21	Research Site	Berlin		Germany	10787
22	Research Site	Berlin		Germany	12627
23	Research Site	Berlin		Germany	13125
24	Research Site	Berlin		Germany	13597
25	Research Site	Bochum		Germany	44787
26	Research Site	Bochum		Germany	44869
27	Research Site	Bonn		Germany	53179
28	Research Site	Bünde		Germany	32257
29	Research Site	Daaden		Germany	57567
30	Research Site	Darmstadt		Germany	64295
31	Research Site	Datteln		Germany	45711
32	Research Site	Deggingen		Germany	73326
33	Research Site	Dippoldiswalde		Germany	01744
34	Research Site	Dortmund		Germany	44137
35	Research Site	Dresden		Germany	01309
36	Research Site	Duisburg		Germany	47179
37	Research Site	Erfurt		Germany	99085
38	Research Site	Erlangen		Germany	91052
39	Research Site	Eschweiler		Germany	52249
40	Research Site	Essen		Germany	45136
41	Research Site	Essen		Germany	45355
42	Research Site	Essen		Germany	45359
43	Research Site	Frankfurt am Main		Germany	60594
44	Research Site	Frankfurt		Germany	60594
45	Research Site	Frankfurt		Germany	60596
46	Research Site	Freiburg im Breisgau		Germany	79106
47	Research Site	Freiburg		Germany	79110
48	Research Site	Freudenstadt		Germany	72250
49	Research Site	Gelnhausen		Germany	63571
50	Research Site	Giengen		Germany	89537
51	Research Site	Goch		Germany	47574
52	Research Site	Grevesmühlen		Germany	23936
53	Research Site	Grossheirath		Germany	96269
54	Research Site	Göttingen		Germany	37073
55	Research Site	Hamburg		Germany	20246
56	Research Site	Hamburg		Germany	21073
57	Research Site	Hamburg		Germany	21109
58	Research Site	Hamburg		Germany	22041
59	Research Site	Hamburg		Germany	22391
60	Research Site	Hamburg		Germany	22607
61	Research Site	Hameln		Germany	31785
62	Research Site	Hannover		Germany	30625
63	Research Site	Heidelberg		Germany	69115
64	Research Site	Herne		Germany	44653
65	Research Site	Hildesheim		Germany	31139
66	Research Site	Hof		Germany	95030
67	Research Site	Hohenmölsen		Germany	06679
68	Research Site	Höhenkirchen		Germany	85635
69	Research Site	Jerichow		Germany	39319
70	Research Site	Kallstadt		Germany	67169
71	Research Site	Karlsruhe		Germany	76199
72	Research Site	Kassel		Germany	34117
73	Research Site	Kiel-Kronshagen		Germany	24119
74	Research Site	Köln		Germany	51069
75	Research Site	Köthen		Germany	06366
76	Research Site	Leipzig		Germany	04103
77	Research Site	Leipzig		Germany	04109
78	Research Site	Lichtenfels		Germany	96215
79	Research Site	Lingen		Germany	49808
80	Research Site	Ludwigshafen		Germany	67059
81	Research Site	Löhne		Germany	32584
82	Research Site	Magdeburg		Germany	39120
83	Research Site	Mannheim		Germany	68161
84	Research Site	Mannheim		Germany	68163
85	Research Site	Marburg		Germany	35037
86	Research Site	Marl		Germany	45770
87	Research Site	Meine		Germany	38527
88	Research Site	Meißen		Germany	01662
89	Research Site	Mühldorf A. Inn		Germany	84453
90	Research Site	München		Germany	80339
91	Research Site	München		Germany	80809
92	Research Site	München		Germany	81477
93	Research Site	Münster		Germany	48143
94	Research Site	Münster		Germany	48153
95	Research Site	Neumünster		Germany	24534
96	Research Site	Neuwied Am Rhein		Germany	56564
97	Research Site	Oldenburg		Germany	23758
98	Research Site	Papenburg		Germany	26871
99	Research Site	Pirna		Germany	01796
100	Research Site	Rehburg Loccum		Germany	31547
101	Research Site	Rehlingen Siersburg		Germany	66780
102	Research Site	Reinfeld		Germany	23858
103	Research Site	Remagen		Germany	53424
104	Research Site	Rhaunen		Germany	55624
105	Research Site	Rodgau-Dudenhofen		Germany	63110
106	Research Site	Saarlouis		Germany	66740
107	Research Site	Schwabenheim		Germany	55270
108	Research Site	Speyer		Germany	67346
109	Research Site	Stadtbergen		Germany	86391
110	Research Site	Stolberg		Germany	52222
111	Research Site	Straubing		Germany	94315
112	Research Site	Stuttgart		Germany	70199
113	Research Site	Sulzbach		Germany	92237
114	Research Site	Trier		Germany	54290
115	Research Site	Villingen-Schwenningen		Germany	78048
116	Research Site	Wahlstedt		Germany	23812
117	Research Site	Wangen		Germany	88239
118	Research Site	Weinheim		Germany	69469
119	Research Site	Westerkappeln		Germany	49492
120	Research Site	Wetzlar		Germany	35584
121	Research Site	Witten		Germany	58455
122	Research Site	Budapest		Hungary	1106
123	Research Site	Budapest		Hungary	1171
124	Research Site	Budapest		Hungary	1213
125	Research Site	Csongrád		Hungary	6640
126	Research Site	Debrecen		Hungary	4025
127	Research Site	Esztergom		Hungary	2500
128	Research Site	Hatvan		Hungary	3000
129	Research Site	Kisvárda		Hungary	4600
130	Research Site	Komárom		Hungary	2921
131	Research Site	Miskolc		Hungary	3529
132	Research Site	Mosonmagyaróvár		Hungary	9200
133	Research Site	Nyíregyháza		Hungary	4405
134	Research Site	Orosháza-Szentetornya		Hungary	5900
135	Research Site	Polgár		Hungary	4090
136	Research Site	Pécs		Hungary	7623
137	Research Site	Székesfehérvár		Hungary	8000
138	Research Site	Ács		Hungary	2941
139	Research Site	Bochnia		Poland	32-700
140	Research Site	Bydgoszcz		Poland	85-231
141	Research Site	Chrzanow		Poland	32-500
142	Research Site	Gdańsk		Poland	80-286
143	Research Site	Koluszki		Poland	95-040
144	Research Site	Krakow		Poland	31-567
145	Research Site	Legnica		Poland	59-220
146	Research Site	Mrągowo		Poland	11-700
147	Research Site	Ostrowiec Świętokrzyski		Poland	27-400
148	Research Site	Poznan		Poland	61655
149	Research Site	Sobótka		Poland	55-050
150	Research Site	Wierzchosławice		Poland	33-122
151	Research Site	Wrocław		Poland	54-144
152	Research Site	Łódź		Poland	90-132
153	Research Site	Banska Bystrica		Slovakia	974 01
154	Research Site	Bratislava		Slovakia	81108
155	Research Site	Bratislava		Slovakia	833 01
156	Research Site	Kosice		Slovakia	040 01
157	Research Site	Kosice		Slovakia	04011
158	Research Site	Kosice		Slovakia
159	Research Site	Levice		Slovakia	934 01
160	Research Site	Levice		Slovakia	934 05
161	Research Site	Lucenec		Slovakia	984 01
162	Research Site	Malacky		Slovakia	901 01
163	Research Site	Namestovo		Slovakia	029 01
164	Research Site	Nove Zamky		Slovakia	94001
165	Research Site	Povazska Bystrica		Slovakia	017 01
166	Research Site	Povazska Bystrica		Slovakia	017 26
167	Research Site	Prievidza		Slovakia	971 01
168	Research Site	Puchov		Slovakia	020 01
169	Research Site	Rimavska Sobota		Slovakia	979 01
170	Research Site	Sabinov		Slovakia	083 01
171	Research Site	Trencin		Slovakia	911 01
172	Research Site	Trnava		Slovakia	917 01
173	Research Site	Vrutky		Slovakia	038 61

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 21, 2017
• Study Protocol - Jan 12, 2017

More Information

Additional Information:

• d1689c00014_SAP_Redacted
• d1689c00014_CSP_Redacted

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02471404
• Other Study ID Numbers: D1689C00014
• First Posted: Jun 15, 2015
• Last Update Posted: Mar 26, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by AstraZeneca: Diabetes Mellitus Type 2,; metformin,; saxagliptin,; dapagliflozin,; glimepiride,; inadequate glycaemic control
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Dapagliflozin; Glimepiride; Saxagliptin

Study Results

Participant Flow

Arm/Group Title	Dapagliflozin 10mg	Saxagliptin 5mg and Dapagliflozin 10mg	Glimepiride 1mg/2mg/4mg
Arm/Group Description	Dapagliflozin 10mg + Metformin	Saxagliptin 5mg and Dapagliflozin 10mg + Metformin	Glimepiride 1mg/2mg/4mg + Metformin
Period Title: Overall Study
STARTED	314	312	313
COMPLETED	281	298	288
NOT COMPLETED	33	14	25

Baseline Characteristics

Arm/Group Title	Dapagliflozin 10mg	Saxagliptin 5mg and Dapagliflozin 10mg	Glimepiride 1mg/2mg/4mg	Total
Arm/Group Description	Dapagliflozin 10mg + Metformin	Saxagliptin 5mg and Dapagliflozin 10mg + Metformin	Glimepiride 1mg/2mg/4mg + Metformin	Total of all reporting groups
Overall Participants	314	312	313	939
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	57.4 (9.36)	59.2 (7.87)	58.6 (8.38)	58.4 (8.58)
Age, Customized (Number) [Number]
<65	232 73.9%	226 72.4%	226 72.2%	684 72.8%
>=65-<75	81 25.8%	86 27.6%	85 27.2%	252 26.8%
>=75	1 0.3%	0 0%	2 0.6%	3 0.3%
Sex: Female, Male (Count of Participants)
Female	112 35.7%	122 39.1%	105 33.5%	339 36.1%
Male	202 64.3%	190 60.9%	208 66.5%	600 63.9%
Race/Ethnicity, Customized (Number) [Number]
Asian	1 0.3%	3 1%	0 0%	4 0.4%
Black Or African American	2 0.6%	2 0.6%	2 0.6%	6 0.6%
White	311 99%	307 98.4%	311 99.4%	929 98.9%

Outcome Measures

1. Primary Outcome

Title	Change in Haemoglobin A1c (HbA1c) From Baseline to Week 52
Description	Change in HbA1c from baseline (week 0) to week 52.
Time Frame	Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Dapaglifozin 10mg	Saxagliptin 5mg and Dapagliflozin 10mg	Glimepiride 1mg/2mg/4mg
Arm/Group Description	Dapaglifozin 10mg + Metformin	Saxagliptin 5mg and Dapagliflozin 10mg + Metformin	Glimepiride 1mg/2mg/4mg + Metformin
Measure Participants	311	312	309
Least Squares Mean (Standard Error) [HbA1c %]	-0.82 (0.049)	-1.2 (0.046)	-0.99 (0.048)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapaglifozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority (NI) margin was determined to be 0.30% (in absolute terms). A difference of ≤0.30%, in HbA1c change from b/l to wk 52 between the treatment groups was considered clinically equivalent. NI was assessed using the 2-sided 95% CI of adjusted mean difference between dapagliflozin or dapagliflozin plus saxagliptin and glimepiride.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; 0.0294 to 0.2986
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Saxagliptin 5mg and Dapagliflozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority (NI) margin was determined to be 0.30% (in absolute terms). A difference of ≤0.30%, in HbA1c change from b/l to wk 52 between the treatment groups was considered clinically equivalent. NI was assessed using the 2-sided 95% Confidence Interval of adjusted mean difference between dapagliflozin or dapagliflozin plus saxagliptin and glimepiride.
Statistical Test of Hypothesis	p-Value	0.001
	Comments	(superiority)
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.3443 to -0.0825
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Patients With at Least One Episode of Confirmed Hypoglycaemia
Description	Percentage of patients reporting at least 1 episode of hypoglycaemia (symptomatic + blood glucose <=50 mg/dL) during the double-blind treatment period
Time Frame	Up to Week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Dapaglifozin 10mg	Saxagliptin 5mg and Dapagliflozin 10mg	Glimepiride 1mg/2mg/4mg
Arm/Group Description	Dapaglifozin 10mg + Metformin	Saxagliptin 5mg and Dapagliflozin 10mg + Metformin	Glimepiride 1mg/2mg/4mg + Metformin
Measure Participants	311	312	309
Number [Percentage of participants]	0 0%	0.32 0.1%	4.21 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapaglifozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-4.21
	Confidence Interval	(2-Sided) 95%; -6.45 to -1.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.14
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Saxagliptin 5mg and Dapagliflozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-3.89
	Confidence Interval	(2-Sided) 95%; -6.21 to -1.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.19
	Estimation Comments

3. Secondary Outcome

Title	Change in Total Body Weight From Baseline at Week 52
Description	Change in body weight from baseline (week 0) to week 52
Time Frame	Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapaglifozin 10mg	Saxagliptin 5mg and Dapagliflozin 10mg	Glimepiride 1mg/2mg/4mg
Arm/Group Description	Dapaglifozin 10mg + Metformin	Saxagliptin 5mg and Dapagliflozin 10mg + Metformin	Glimepiride 1mg/2mg/4mg + Metformin
Measure Participants	311	312	309
Least Squares Mean (Standard Error) [Weight (kg)]	-3.54 (0.231)	-3.15 (0.219)	1.76 (0.224)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapaglifozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.30
	Confidence Interval	(2-Sided) 95%; -5.93 to -4.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Saxagliptin 5mg and Dapagliflozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.91
	Confidence Interval	(2-Sided) 95%; -5.52 to -4.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52
Description	Change in FPG from baseline (week 0) to week 52
Time Frame	Baseline, week 52. Values recorded after rescue treatment or collected more than 8 days after the last dose date were excluded from the analysis

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Dapaglifozin 10mg	Saxagliptin 5mg and Dapagliflozin 10mg	Glimepiride 1mg/2mg/4mg
Arm/Group Description	Dapaglifozin 10mg + Metformin	Saxagliptin 5mg and Dapagliflozin 10mg + Metformin	Glimepiride 1mg/2mg/4mg + Metformin
Measure Participants	311	312	309
Least Squares Mean (Standard Error) [FPG (mmol/L)]	-1.62 (0.106)	-2.08 (0.100)	-1.49 (0.105)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapaglifozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.374
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Saxagliptin 5mg and Dapagliflozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.59
	Confidence Interval	(2-Sided) 95%; -0.88 to -0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Time to Rescue
Description	The time to rescue (from first dose date after randomisation to start of rescue medication or discontinuation due to lack of glycaemic control) during the 52 week double blind treatment period
Time Frame	Over the 52 week treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapaglifozin 10mg	Saxagliptin 5mg and Dapagliflozin 10mg	Glimepiride 1mg/2mg/4mg
Arm/Group Description	Dapaglifozin 10mg + Metformin	Saxagliptin 5mg and Dapagliflozin 10mg + Metformin	Glimepiride 1mg/2mg/4mg + Metformin
Measure Participants	311	312	309
Median (95% Confidence Interval) [Weeks]	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapaglifozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.777
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Saxagliptin 5mg and Dapagliflozin 10mg, Glimepiride 1mg/2mg/4mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.23 to 0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Patients Rescued
Description	Number (%) of patients rescued.
Time Frame	Over the 52 week treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapaglifozin 10mg	Saxagliptin 5mg and Dapagliflozin 10mg	Glimepiride 1mg/2mg/4mg
Arm/Group Description	Dapaglifozin 10mg + Metformin	Saxagliptin 5mg and Dapagliflozin 10mg + Metformin	Glimepiride 1mg/2mg/4mg + Metformin
Measure Participants	311	312	309
Number [Percentage of participants]	18.6 5.9%	8.3 2.7%	21.4 6.8%

Adverse Events

Time Frame	Adverse Events from signature of informed consent, enrolment, randomisation and throughout the 52 week treatment period and including the follow-up period. Serious Adverse Events from the time of informed consent.
Adverse Event Reporting Description	Safety Analysis Set (All randomised subjects who received at least 1 dose of study medication) N=313, 312, 312 for Dapa, Saxa+Dapa, Glim respectively. subjects excluded from the Safety Analysis Set (n=1,0, 1 for Dapa, Saxa+Dapa, Glim respectively) did not receive treatment.
Arm/Group Title	Dapagliflozin 10mg		Saxagliptin 5mg and Dapagliflozin 10mg		Glimepiride 1mg/2mg/4mg
Arm/Group Description	Dapagliflozin 10mg + Metformin		Saxagliptin 5mg and Dapagliflozin 10mg + Metformin		Glimepiride 1mg/2mg/4mg + Metformin
All Cause Mortality
	Dapagliflozin 10mg		Saxagliptin 5mg and Dapagliflozin 10mg		Glimepiride 1mg/2mg/4mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/313 (0%)		0/312 (0%)		0/312 (0%)
Serious Adverse Events
	Dapagliflozin 10mg		Saxagliptin 5mg and Dapagliflozin 10mg		Glimepiride 1mg/2mg/4mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/313 (12.5%)		22/312 (7.1%)		35/312 (11.2%)
Cardiac disorders
Acute coronary syndrome	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Acute myocardial infarction	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Angina pectoris	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Atrial fibrillation	0/313 (0%)	0	0/312 (0%)	0	2/312 (0.6%)	2
Bradyarrhythmia	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Cardiac failure congestive	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Coronary artery disease	1/313 (0.3%)	1	3/312 (1%)	3	2/312 (0.6%)	2
Coronary artery occlusion	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Myocardial ischaemia	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Endocrine disorders
Basedow's disease	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Goitre	0/313 (0%)	0	1/312 (0.3%)	1	1/312 (0.3%)	1
Thyroid haemorrhage	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Eye disorders
Vitritis	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Gastrointestinal disorders
Anal fistula	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Gastric ulcer	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Gastritis	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Pancreatitis	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Vomiting	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Hepatobiliary disorders
Cholecystitis	0/313 (0%)	0	0/312 (0%)	0	2/312 (0.6%)	2
Cholelithiasis	1/313 (0.3%)	1	1/312 (0.3%)	1	1/312 (0.3%)	1
Infections and infestations
Abscess neck	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Appendicitis	0/313 (0%)	0	1/312 (0.3%)	1	1/312 (0.3%)	1
Endocarditis	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Erysipelas	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Gastroenteritis clostridial	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Micrococcus infection	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Pneumonia	1/313 (0.3%)	1	0/312 (0%)	0	1/312 (0.3%)	1
Reiter's syndrome	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Scrotal abscess	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Urinary tract infection	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Injury, poisoning and procedural complications
Brain contusion	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Epicondylitis	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Femoral neck fracture	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Post procedural complication	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Respiratory fume inhalation disorder	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Rib fracture	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Tendon injury	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Tendon rupture	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Metabolism and nutrition disorders
Diabetes mellitus	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Back pain	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Dupuytren's contracture	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Fibromyalgia	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Intervertebral disc protrusion	2/313 (0.6%)	2	2/312 (0.6%)	2	2/312 (0.6%)	2
Muscle rigidity	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Osteoarthritis	1/313 (0.3%)	1	1/312 (0.3%)	1	2/312 (0.6%)	2
Plantar fasciitis	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Adenocarcinoma	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Bladder transitional cell carcinoma	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Endometrial adenocarcinoma	1/313 (0.3%)	1	0/312 (0%)	0	1/312 (0.3%)	1
Malignant melanoma	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Melanoma recurrent	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Renal neoplasm	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Thyroid cancer	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Nervous system disorders
Brain stem infarction	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Cerebral ischaemia	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Cerebrovascular accident	2/313 (0.6%)	2	0/312 (0%)	0	0/312 (0%)	0
Essential tremor	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Headache	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Restless legs syndrome	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Seizure	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Syncope	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Transient ischaemic attack	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Vertebrobasilar insufficiency	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Psychiatric disorders
Depression	1/313 (0.3%)	1	1/312 (0.3%)	1	0/312 (0%)	0
Somatic symptom disorder	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Renal and urinary disorders
Bladder prolapse	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Nephrolithiasis	1/313 (0.3%)	1	0/312 (0%)	0	1/312 (0.3%)	1
Renal impairment	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Ureterolithiasis	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Urethral stenosis	2/313 (0.6%)	2	0/312 (0%)	0	0/312 (0%)	0
Urinary incontinence	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Reproductive system and breast disorders
Acquired phimosis	1/313 (0.3%)	1	0/312 (0%)	0	0/312 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/313 (0%)	0	0/312 (0%)	0	1/312 (0.3%)	1
Pulmonary embolism	0/313 (0%)	0	0/312 (0%)	0	2/312 (0.6%)	2
Skin and subcutaneous tissue disorders
Diabetic foot	1/313 (0.3%)	1	0/312 (0%)	1	0/312 (0%)	0
Vascular disorders
Hypertensive crisis	0/313 (0%)	0	1/312 (0.3%)	1	0/312 (0%)	0
Peripheral arterial occlusive disease	0/313 (0%)	0	1/312 (0.3%)	1	1/312 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Dapagliflozin 10mg		Saxagliptin 5mg and Dapagliflozin 10mg		Glimepiride 1mg/2mg/4mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/313 (9.3%)		31/312 (9.9%)		37/312 (11.9%)
Infections and infestations
Nasopharyngitis	29/313 (9.3%)	40	31/312 (9.9%)	39	37/312 (11.9%)	49

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.