BEST: Bexagliflozin Efficacy and Safety Trial

Sponsor

Theracos (Industry)

Overall Status

Completed

CT.gov ID

NCT02558296

Collaborator

(none)

1,700

Enrollment

157

Locations

Arms

48.7

Actual Duration (Months)

10.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the effect of bexagliflozin in lowering hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM) and increased risk of cardiovascular adverse events.

The data from this study will be combined with the data from other bexagliflozin studies in a meta-analysis of CV safety outcomes.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Bexagliflozin Drug: Placebo	Phase 3

Detailed Description

Approximately 130 investigative sites globally are planned to participate in this study.

An estimated 1650 subjects with inadequately controlled T2DM and an elevated risk of cardiovascular adverse events will be randomized to bexagliflozin tablets, 20 mg, or placebo in a ratio of 2:1 in addition to the background anti-diabetic medications.

The study is an event-driven trial. The treatment period will end when the last randomized subject has completed at least 52 weeks of treatment and a total of at least 134 subjects have experienced a cardiac event.

Study Design

Study Type:

Interventional

Actual Enrollment :

1700 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Double Blind Placebo Controlled Study to Evaluate the Effects of Bexagliflozin on Hemoglobin A1c in Patients With Type 2 Diabetes and Increased Risk of Cardiovascular Adverse Events

Actual Study Start Date :

Oct 1, 2015

Actual Primary Completion Date :

Aug 1, 2018

Actual Study Completion Date :

Oct 23, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bexagliflozin tablets, 20 mg Each subject will receive bexagliflozin 20 mg once daily for the duration of the study.	Drug: Bexagliflozin 20 mg, tablet Other Names: EGT0001442 EGT0001474
Placebo Comparator: Placebo tablets Each subject will receive placebo (inactive tablet) once daily for the duration of the study.	Drug: Placebo 20 mg tablet to match active comparator

Arm

Intervention/Treatment

Active Comparator: Bexagliflozin tablets, 20 mg

Each subject will receive bexagliflozin 20 mg once daily for the duration of the study.

Drug: Bexagliflozin

20 mg, tablet

Other Names:

EGT0001442

EGT0001474

Placebo Comparator: Placebo tablets

Each subject will receive placebo (inactive tablet) once daily for the duration of the study.

Drug: Placebo

20 mg tablet to match active comparator

Outcome Measures

Primary Outcome Measures

Change in HbA1c From Baseline to Week 24 [24 weeks]
The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in HbA1c from baseline after 24 weeks of treatment with 20 mg bexagliflozin tablets in type 2 diabetic subjects with increased risk of cardiovascular adverse events.

Secondary Outcome Measures

Change From Baseline in HbA1c at Week 24 for Subjects Who Have Been Prescribed Insulin [24 weeks]
To evaluate the effect of 20 mg bexagliflozin on the change in HbA1c from baseline to week 24 in randomized subjects who have been prescribed insulin to control their diabetes
Change in Body Weight From Baseline to Week 48 [48 weeks]
To evaluate the effect of 20 mg bexagliflozin on the change in body weight from baseline to week 48 in randomized subjects with a BMI ≥ 25 kg/m2 compared to placebo
Change in Systolic Blood Pressure From Baseline to Week 24 in Subjects Hypertensive at Baseline [24 weeks]
To evaluate the effect of 20 mg bexagliflozin on the change in systolic blood pressure (SBP) from baseline to week 24 in subjects with baseline systolic blood pressure ≥ 140 mmHg compared to placebo

Other Outcome Measures

Change in HbA1c From Baseline Over Time [Baseline (week 0) and weeks 6, 12, 24, 36, 48, 72, 96, 120, 144 and 168]
To assess the effect of 20 mg bexagliflozin treatment on the change in HbA1c from baseline versus placebo over time up to 168 weeks
Change in Fasting Plasma Glucose Over Time [Baseline (week 0) and weeks 6, 12, 24, 36, 48, 72, 96, 120, 144 and 168]
To evaluate the effect of bexagliflozin treatment on the change in fasting plasma glucose (FPG) versus placebo over time up to 168 weeks
Proportion of Subjects Requiring an Intensification of Hypoglycemic Agent and Time to First Intensification [24 week]
To measure the proportion of subjects requiring an intensification of hypoglycemic agent in the bexagliflozin arm versus placebo during 24 week period
Proportion of Subjects Requiring an Intensification of Hypoglycemic Agent and Time to First Intensification [Duration of study (168 weeks)]
To measure the proportion of subjects requiring an intensification of hypoglycemic agent in the bexagliflozin arm versus placebo during the entire study period
Proportion of Subjects Requiring a Relaxation of Hypoglycemic Agent [24 weeks]
To measure the proportion of subjects requiring a relaxation of hypoglycemic agent in the bexagliflozin arm versus placebo during 24 week period
Proportion of Subjects Requiring a Relaxation of Hypoglycemic Agent [Duration of study (168 weeks)]
To measure the proportion of subjects requiring a relaxation of hypoglycemic agent in the bexagliflozin arm versus placebo during the entire study
Proportion of Participants With Incidence of Hospitalization for Heart Failure [Duration of study (168 weeks)]
To measure the incidence of hospitalization for heart failure among all subjects and among subjects who have a history of heart failure at baseline

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subjects with a diagnosis of T2DM
Subjects who have had a stable treatment regimen for T2DM for the past 3 months
Subjects who present with at least one of the following 3 histories:

Group 1: A history of atherosclerotic vascular disease Group 2: A history of heart failure Group 3: Age ≥ 55 years with diabetes for ≥ 10 years, uncontrolled hypertension, currently smoking, reduced kidney function, or cholesterol problems

Exclusion Criteria:

Diagnosis of type 1 diabetes mellitus or maturity-onset/diabetes of the young
History of genitourinary tract infections
Evidence of abnormal liver function
History of MI, stroke or hospitalization for heart failure in the past 3 months
Prior kidney transplant or evidence of kidney problems
Prior or planned pace maker implantation
Pregnant or nursing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site 1090	Gilbert	Arizona	United States	85295
2	Research Site 1041	Little Rock	Arkansas	United States	72204
3	Research Site 1073	Azusa	California	United States	91773
4	Research Site 1076	Concord	California	United States	94520
5	Research Site 1078	Fresno	California	United States	93720
6	Research Site 1089	Harbor City	California	United States	90710
7	Research Site 1058	Lincoln	California	United States	95821
8	Research Site 1051	Los Angeles	California	United States	90022
9	Research Site 1004	Los Angeles	California	United States	90057
10	Research Site 1068	Montclair	California	United States	91763
11	Research Site 1077	Orange	California	United States	92868
12	Research Site 1218	Denver	Colorado	United States	80209
13	Research Site 1092	Golden	Colorado	United States	80401
14	Research Site 1216	Norwalk	Connecticut	United States	06851
15	Research Site 1083	Newark	Delaware	United States	19713
16	Research Site 1057	Boca Raton	Florida	United States	33434
17	Research Site 1059	Brooksville	Florida	United States	34601
18	Research Site 1050	Panama City	Florida	United States	32401
19	Research Site 1099	Port Charlotte	Florida	United States	33952
20	Research Site 1066	Tampa	Florida	United States	33634
21	Research Site 1072	Augusta	Georgia	United States	30909
22	Research Site 1082	Pocatello	Idaho	United States	83201
23	Research Site 1258	Champaign	Illinois	United States	61822
24	Research Site 1043	Anderson	Indiana	United States	46011
25	Research Site 1071	Avon	Indiana	United States	46123
26	Research Site 1086	Des Moines	Iowa	United States	50314
27	Research Site 1224	Covington	Kentucky	United States	41011
28	Research Site 1228	Annapolis	Maryland	United States	21401
29	Research Site 1221	Baltimore	Maryland	United States	21202
30	Research Site 1079	Hyattsville	Maryland	United States	20782
31	Research Site 1223	Midland	Michigan	United States	48670
32	Research Site 1217	Petoskey	Michigan	United States	49770
33	Research Site 1254	Ypsilanti	Michigan	United States	48197
34	Research Site 1054	Saint Louis	Missouri	United States	63136
35	Research Site 1060	Saint Louis	Missouri	United States	63141
36	Research Site 1252	Kalispell	Montana	United States	59901
37	Research Site 1052	Omaha	Nebraska	United States	68131
38	Research Site 1263	Omaha	Nebraska	United States	68198
39	Research Site 1080	Las Vegas	Nevada	United States	89123
40	Research Site 1219	Somerset	New Jersey	United States	08873
41	Research Site 1044	Albuquerque	New Mexico	United States	87102
42	Research Site 1264	Bronx	New York	United States	10468
43	Research Site 1220	Saratoga Springs	New York	United States	12866
44	Research Site 1049	West Seneca	New York	United States	14224
45	Research Site 1085	Chapel Hill	North Carolina	United States	27517
46	Research Site 1074	Charlotte	North Carolina	United States	28204
47	Research Site 1056	Morehead City	North Carolina	United States	28557
48	Research Site 1229	Wilmington	North Carolina	United States	28401
49	Research Site 1064	Winston-Salem	North Carolina	United States	27103
50	Research Site 1075	Fargo	North Dakota	United States	58103
51	Research Site 1266	Lindsay	Oklahoma	United States	73052
52	Research Site 1055	Oklahoma City	Oklahoma	United States	73119
53	Research Site 1265	Oklahoma City	Oklahoma	United States	73134
54	Research Site 1046	Oklahoma City	Oklahoma	United States	73135
55	Research Site 1260	Lancaster	Pennsylvania	United States	17601
56	Research Site 1042	Cumberland	Rhode Island	United States	02864
57	Research Site 1225	Austin	Texas	United States	78758
58	Research Site 1259	Dallas	Texas	United States	75235
59	Research Site 1048	Kingwood	Texas	United States	77339
60	Research Site 1070	Lampasas	Texas	United States	76550
61	Research Site 1222	Lewisville	Texas	United States	75067
62	Research Site 1081	North Richland Hills	Texas	United States	76180
63	Research Site 1226	San Antonio	Texas	United States	78212
64	Research Site 1053	San Antonio	Texas	United States	78218
65	Research Site 1063	Salt Lake City	Utah	United States	84124
66	Research Site 1230	Salem	Virginia	United States	24153
67	Research Site 5013	Vancouver	British Columbia	Canada	V5Z1M9
68	Research Site 5015	Cambridge	Ontario	Canada	N1R 6V6
69	Research Site 5012	Hamilton	Ontario	Canada	L8L5G8
70	Research Site 5023	London	Ontario	Canada	N6A 4V2
71	Research Site 5016	Peterborough	Ontario	Canada	K9J 0B2
72	Research Site 5005	Sudbury	Ontario	Canada	P3C 5K7
73	Research Site 5022	Toronto	Ontario	Canada	M5B 1W8
74	Research Site 5014	Toronto	Ontario	Canada	M5G 1XS
75	Research Site 5008	Gatineau	Quebec	Canada	J8Y 6S8
76	Research Site 5007	St-Charles-Borromee	Quebec	Canada	J6E 6J2
77	Research Site 5009	St. Georges	Quebec	Canada	G5Y4T8
78	Research Site 5006	Quebec		Canada	G1V 4G5
79	Research Site 3116	Benesov		Czechia	256 01
80	Research Site 3106	Brandys nad Labem		Czechia	250 01
81	Research Site 3107	Brno		Czechia	60200
82	Research Site 3118	Brno		Czechia	639 00
83	Research Site 3109	Cesky Krumlov		Czechia	381 01
84	Research Site 3114	Havirov		Czechia	736 01
85	Research Site 3103	Hradec Kralove		Czechia	50005
86	Research Site 3110	Krnov		Czechia	794 01
87	Research Site 3102	Kromeriz		Czechia	767 01
88	Research Site 3105	Marianske Lazne		Czechia	353 01
89	Research Site 3113	Plzen		Czechia	326 00
90	Research Site 3104	Praha		Czechia	128 08
91	Research Site 3111	Praha		Czechia	149 00
92	Research Site 3112	Praha		Czechia	181 00
93	Research Site 3115	Uherske Hradiste		Czechia	686 68
94	Research Site 6104	Copenhagen		Denmark	2100
95	Research Site 6103	Copenhagen		Denmark	2300S
96	Research Site 6105	Copenhagen		Denmark	2400
97	Research Site 7007	Chuncheon	Gangwon-Do	Korea, Republic of	200-722
98	Research Site 7001	Wonju	Gangwon-Do	Korea, Republic of	220-701
99	Research Site 7004	Anyang	Gyeonggi-do	Korea, Republic of	431-070
100	Research Site 7005	Guri	Gyeonggi-do	Korea, Republic of	471-701
101	Research Site 7006	Busan		Korea, Republic of	602-739
102	Research Site 7002	Gwangju		Korea, Republic of	501-757
103	Research Site 7008	Incheon		Korea, Republic of	400-711
104	Research Site 2015	Guadalajara	Jalisco	Mexico	44160
105	Research Site 2013	Culiacan	Sinaloa	Mexico	80230
106	Research Site 2008	Tampico	Tamaulipas	Mexico	89000
107	Research Site 2012	Merida	Yucatan	Mexico	97218
108	Research Site 2011	Aguascalientes		Mexico	20230
109	Research Site 2009	Chihuahua		Mexico	31217
110	Research Site 2014	Mexico		Mexico	80230
111	Research Site 2016	Queretaro		Mexico
112	Research Site 2010	Veracruz		Mexico	91910
113	Research Site 5110	Amsterdam		Netherlands	2545CH
114	Research Site 5113	Harderwijk		Netherlands	3844DG
115	Research Site 5101	Hertogenbosch		Netherlands	5223GZ
116	Research Site 5112	Hoofddorp		Netherlands
117	Research Site 5102	Hoogeveen		Netherlands	7909AA
118	Research Site 5106	Rotterdam		Netherlands	3O45 PM
119	Research Site 5103	Zwijndrecht		Netherlands	3331EV
120	Research Site 7122	Aleksandrow Lodzki		Poland	95-070
121	Research Site 7113	Gdansk		Poland	80-126
122	Research Site 7119	Gdynia		Poland	81-338
123	Research Site 7109	Grodzisk Mazowiecki		Poland	05-825
124	Research Site 7115	Katowice		Poland	20-060
125	Research Site 7106	Katowice		Poland	40-752
126	Research Site 7121	Katowice		Poland	40-954
127	Research Site 7111	Kutno		Poland	99-300
128	Research Site 7104	Lodz		Poland	90-368
129	Research Site 7135	Lodz		Poland	94-255
130	Research Site 7120	Lublin		Poland	20-362
131	Research Site 7108	Olawa		Poland	55-200
132	Research Site 7118	Otwock		Poland	05-402
133	Research Site 7107	Pulawy		Poland	24-100
134	Research Site 7105	Sobotka		Poland	55-050
135	Research Site 7112	Sochaczew		Poland	96-500
136	Research Site 7123	Warsaw		Poland	00-465
137	Research Site 7117	Warszawa		Poland	01-868
138	Research Site 7116	Warszawa		Poland	04-730
139	Research Site 9309	Lomonosov		Russian Federation
140	Research Site 9303	Moscow		Russian Federation
141	Research Site 9315	Moscow		Russian Federation
142	Research Site 9314	Novosibirsk		Russian Federation	630099
143	Research Site 9318	Novosibirsk		Russian Federation	630099
144	Research Site 9301	Novosibirsk		Russian Federation
145	Research Site 9310	Saint Petersburg		Russian Federation	1199044
146	Research Site 9304	Saint Petersburg		Russian Federation
147	Research Site 9307	Saint Petersburg		Russian Federation
148	Research Site 9311	Saint Petersburg		Russian Federation
149	Research Site 9312	Saint Petersburg		Russian Federation
150	Research Site 9302	Tomsk		Russian Federation	6340
151	Research Site 8001	Kaohsiung		Taiwan	807
152	Research Site 8002	New Taipei		Taiwan	231
153	Research Site 8006	Taichung		Taiwan	404
154	Research Site 8005	Tainan		Taiwan	704
155	Research Site 8007	Taipei		Taiwan	100
156	Research Site 8004	Taipei		Taiwan	111
157	Research Site 8003	Taipei		Taiwan	112

Sponsors and Collaborators

Theracos

Investigators

Study Director: J. Paul Lock, MD, Theracos

Study Documents (Full-Text)

Study Protocol and Statistical Analysis Plan - Nov 20, 2019

More Information

Publications

None provided.

Responsible Party:

Theracos

ClinicalTrials.gov Identifier:

NCT02558296

Other Study ID Numbers:

THR-1442-C-476

First Posted:

Sep 23, 2015

Last Update Posted:

Jul 14, 2021

Last Verified:

Jul 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Additional relevant MeSH terms:

Diabetes Mellitus, Type 2

Bexagliflozin

Study Results

Participant Flow

Recruitment Details	A total of 1700 patients were recruited from 10 countries: Canada, Czech Republic, Demark, Republic of Korea, Mexico, the Netherlands, Poland, Russian Federation, Taiwan, and the United States.
Pre-assignment Detail	Subjects ≥ 40 years old with inadequately controlled T2DM with HbA1c between 7.5% (7.0% since protocol version 8) and 11% on stable medications and elevated risk for CV adverse events were enrolled. All subjects must belong to 1 of 3 CV risk groups to be eligible. All eligible subjects took placebo during 13 ± 2 days run-in period.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Period Title: Completed the Study Through Week 24
STARTED	1133	567
COMPLETED	1089	542
NOT COMPLETED	44	25
Period Title: Completed the Study Through Week 24
STARTED	1133	567
COMPLETED	987	482
NOT COMPLETED	146	85

Baseline Characteristics

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets	Total
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator	Total of all reporting groups
Overall Participants	1133	567	1700
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	562 49.6%	276 48.7%	838 49.3%
>=65 years	571 50.4%	291 51.3%	862 50.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.4 (7.94)	64.6 (8.01)	64.4 (7.96)
Sex: Female, Male (Count of Participants)
Female	341 30.1%	177 31.2%	518 30.5%
Male	792 69.9%	390 68.8%	1182 69.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	166 14.7%	93 16.4%	259 15.2%
Not Hispanic or Latino	967 85.3%	474 83.6%	1441 84.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	98 8.6%	54 9.5%	152 8.9%
Asian	108 9.5%	55 9.7%	163 9.6%
Native Hawaiian or Other Pacific Islander	2 0.2%	0 0%	2 0.1%
Black or African American	46 4.1%	28 4.9%	74 4.4%
White	879 77.6%	430 75.8%	1309 77%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Canada	67 5.9%	24 4.2%	91 5.4%
Netherlands	36 3.2%	18 3.2%	54 3.2%
South Korea	48 4.2%	26 4.6%	74 4.4%
United States	397 35%	205 36.2%	602 35.4%
Czechia	118 10.4%	52 9.2%	170 10%
Taiwan	46 4.1%	20 3.5%	66 3.9%
Denmark	17 1.5%	10 1.8%	27 1.6%
Poland	196 17.3%	97 17.1%	293 17.2%
Mexico	121 10.7%	62 10.9%	183 10.8%
Russia	87 7.7%	53 9.3%	140 8.2%
Cardiovascular Risk Groups (Count of Participants)
Group 1: History of atherosclerotic vascular disease	703 62%	362 63.8%	1065 62.6%
Group 2: History of heart failure	166 14.7%	80 14.1%	246 14.5%
Group 3: Age >= 55 years with > 2 risk factors	264 23.3%	125 22%	389 22.9%
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	94.59 (21.87)	92.62 (19.999)	93.94 (20.745)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	32.80 (6.068)	32.24 (5.751)	32.62 (5.968)
Body Mass Index Categories (Count of Participants)
BMI < 25 kg/m^2	86 7.6%	45 7.9%	131 7.7%
BMI >= 25 kg/m^2	1047 92.4%	522 92.1%	1569 92.3%
Systolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	134.2 (16.24)	133.7 (16.18)	134.0 (16.21)
Systolic Blood Pressure Groups (Count of Participants)
< 140 mmHg	685 60.5%	352 62.1%	1037 61%
>= 140 mmHg	448 39.5%	215 37.9%	663 39%
Diastolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	77.1 (9.94)	76.8 (10.16)	77.0 (10.01)
eGFR at Screening (mL/min/1.73 m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73 m^2]	77.93 (19.475)	77.76 (19.653)	77.88 (19.529)
eGFR group (Count of Participants)
< 60 mL/min/1.73 m^2	225 19.9%	109 19.2%	334 19.6%
>= 60 mL/min/1.73 m^2	908 80.1%	458 80.8%	1366 80.4%
HbA1c (% of HbA1c) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% of HbA1c]	8.32 (0.897)	8.33 (0.944)	8.32 (0.913)
HbA1c group (Count of Participants)
<= 8.5%	716 63.2%	362 63.8%	1078 63.4%
> 8.5%	417 36.8%	205 36.2%	622 36.6%
Duration of Diabetes from Diagnosis to the date of informed consent (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.87 (8.635)	15.23 (9.253)	14.99 (8.845)
Insulin Use at Baseline (Count of Participants)
Yes	610 53.8%	292 51.5%	902 53.1%
No	523 46.2%	275 48.5%	798 46.9%
Use of Anti-Diabetic Treatment at Baseline (Count of Participants)
Yes	1125 99.3%	564 99.5%	1689 99.4%
No	8 0.7%	3 0.5%	11 0.6%
NT-proBNP (pmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pmol/L]	391.9 (760.75)	264.0 (427.15)	346.1 (661.93)
Left Ventricular Ejection Fraction (% of Left Ventricular Ejection Fraction) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% of Left Ventricular Ejection Fraction]	49.2 (14.13)	50.8 (12.95)	49.8 (13.74)

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c From Baseline to Week 24
Description	The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in HbA1c from baseline after 24 weeks of treatment with 20 mg bexagliflozin tablets in type 2 diabetic subjects with increased risk of cardiovascular adverse events.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description
Number of subjects with a value at baseline and at Week 24.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	1046	531
Least Squares Mean (95% Confidence Interval) [percentage of glycated hemoglobin]	-0.85	-0.37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the primary endpoint was that the mean change in HbA1c from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 24 was less than the mean change in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95% -0.56 to -0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in HbA1c at Week 24 for Subjects Who Have Been Prescribed Insulin
Description	To evaluate the effect of 20 mg bexagliflozin on the change in HbA1c from baseline to week 24 in randomized subjects who have been prescribed insulin to control their diabetes
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description
Number of subjects with a value at baseline and at week 24.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	561	273
Least Squares Mean (95% Confidence Interval) [Percentage of HbA1c]	-0.84	-0.32

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the secondary endpoint was that the mean change in HbA1c from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 24 was less than the mean change in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories, history of heart failure, treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95% -0.65 to -0.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Body Weight From Baseline to Week 48
Description	To evaluate the effect of 20 mg bexagliflozin on the change in body weight from baseline to week 48 in randomized subjects with a BMI ≥ 25 kg/m2 compared to placebo
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description
Number of subjects with a value at baseline and at Week 48 is included.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	922	456
Least Squares Mean (95% Confidence Interval) [kg]	-3.03	-0.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the secondary endpoint was that the mean change in body weight from baseline to Week 48 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in body weight from baseline to Week 48 was less than the mean change in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is presented based on one-sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline HbA1c and eGFR, history of heart failure, insulin use (Y/N), treatment, visit and baseline body weight as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.65
	Confidence Interval	(2-Sided) 95% -3.07 to -2.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Systolic Blood Pressure From Baseline to Week 24 in Subjects Hypertensive at Baseline
Description	To evaluate the effect of 20 mg bexagliflozin on the change in systolic blood pressure (SBP) from baseline to week 24 in subjects with baseline systolic blood pressure ≥ 140 mmHg compared to placebo
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description
Number of subjects with a value at baseline and at week 24

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	417	204
Least Squares Mean (95% Confidence Interval) [mm Hg]	-9.83	-6.87

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the secondary endpoint was that the mean change in systolic blood pressure from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in systolic blood pressure from baseline to Week 24 was less than the mean change in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	0.0112
	Comments	P-value is presented based on one-sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline HbA1c, GFR categories, BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline SBP as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.96
	Confidence Interval	(2-Sided) 95% -5.51 to -0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Other Pre-specified Outcome

Title	Change in HbA1c From Baseline Over Time
Description	To assess the effect of 20 mg bexagliflozin treatment on the change in HbA1c from baseline versus placebo over time up to 168 weeks
Time Frame	Baseline (week 0) and weeks 6, 12, 24, 36, 48, 72, 96, 120, 144 and 168

Outcome Measure Data

Analysis Population Description
Number of subjects with a value at baseline and at the specified visit.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	1133	567
Week 6	-0.69	-0.24
Week 12	-0.89	-0.34
Week 24	-0.84	-0.37
Week 36	-0.86	-0.39
Week 48	-0.84	-0.38
Week 72	-0.76	-0.34
Week 96	-0.68	-0.29
Week 120	-0.65	-0.22
Week 144	-0.62	-0.23
Week 168	-0.56	-0.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 6 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 6 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.45
	Confidence Interval	(2-Sided) 95% -0.50 to -0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 12 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 12 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95% -0.63 to -0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 24 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95% -0.56 to -0.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 36 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 36 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95% -0.56 to -0.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 48 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 48 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95% -0.56 to -0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 72 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 72 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95% -0.54 to -0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 96 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 96 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95% -0.51 to -0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 120 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 120 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95% -0.56 to -0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 144 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 144 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95% -0.54 to -0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 168 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 168 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	0.0045
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95% -0.47 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

Title	Change in Fasting Plasma Glucose Over Time
Description	To evaluate the effect of bexagliflozin treatment on the change in fasting plasma glucose (FPG) versus placebo over time up to 168 weeks
Time Frame	Baseline (week 0) and weeks 6, 12, 24, 36, 48, 72, 96, 120, 144 and 168

Outcome Measure Data

Analysis Population Description
Number of subjects with a value at baseline and at the specified visit.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	1133	567
Week 6	-1.28	0.07
Week 12	-1.33	0.06
Week 24	-1.43	-0.05
Week 36	-1.21	-0.06
Week 48	-1.36	-0.12
Week 72	-1.14	-0.15
Week 96	-1.16	0.04
Week 120	-0.90	0.25
Week 144	-1.03	-0.40
Week 168	-1.06	-0.55

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 6 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 6 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.35
	Confidence Interval	(2-Sided) 95% -1.55 to -1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 12 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 12 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95% -1.61 to -1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 24 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95% -1.61 to -1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 36 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 36 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.15
	Confidence Interval	(2-Sided) 95% -1.41 to -0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 48 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 48 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.23
	Confidence Interval	(2-Sided) 95% -1.48 to -0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 72 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 72 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.99
	Confidence Interval	(2-Sided) 95% -1.27 to -0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 96 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 96 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.20
	Confidence Interval	(2-Sided) 95% -1.50 to -0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 120 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 120 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.15
	Confidence Interval	(2-Sided) 95% -1.49 to -0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 144 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 144 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	0.0008
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.63
	Confidence Interval	(2-Sided) 95% -1.01 to -0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 168 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 168 was less than that in the placebo arm by a value that could not be attributed to chance alone.

Statistical Test of Hypothesis	p-Value	0.0462
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95% -1.09 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Other Pre-specified Outcome

Title	Proportion of Subjects Requiring an Intensification of Hypoglycemic Agent and Time to First Intensification
Description	To measure the proportion of subjects requiring an intensification of hypoglycemic agent in the bexagliflozin arm versus placebo during 24 week period
Time Frame	24 week

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	1133	567
Number (95% Confidence Interval) [Proportion of participants]	0.06 0%	0.18 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Logistic
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95% 0.22 to 0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is calculated as the odds ratio of bexagliflozin over placebo.

8. Other Pre-specified Outcome

Title	Proportion of Subjects Requiring an Intensification of Hypoglycemic Agent and Time to First Intensification
Description	To measure the proportion of subjects requiring an intensification of hypoglycemic agent in the bexagliflozin arm versus placebo during the entire study period
Time Frame	Duration of study (168 weeks)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	1133	567
Number (95% Confidence Interval) [Proportion of participants]	0.06 0%	0.18 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Cox
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95% 0.35 to 0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio and p-value were estimated using Cox regression model for time to first event in the bexagliflozin arm vs. placebo arm during entire study.

9. Other Pre-specified Outcome

Title	Proportion of Subjects Requiring a Relaxation of Hypoglycemic Agent
Description	To measure the proportion of subjects requiring a relaxation of hypoglycemic agent in the bexagliflozin arm versus placebo during 24 week period
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	1133	567
Number (95% Confidence Interval) [Proportion of participants]	0.09 0%	0.05 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0005
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Logistic
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.04
	Confidence Interval	(2-Sided) 95% 1.33 to 3.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is calculated as the ratio of bexagliflozin over placebo.

10. Other Pre-specified Outcome

Title	Proportion of Subjects Requiring a Relaxation of Hypoglycemic Agent
Description	To measure the proportion of subjects requiring a relaxation of hypoglycemic agent in the bexagliflozin arm versus placebo during the entire study
Time Frame	Duration of study (168 weeks)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Measure Participants	1133	567
Number (95% Confidence Interval) [Proportion of participants]	0.09 0%	0.05 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Cox
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.82
	Confidence Interval	(2-Sided) 95% 1.40 to 2.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio and p-value were estimated using Cox regression model for time to first event in the bexagliflozin arm vs. placebo arm during the entire study.

11. Other Pre-specified Outcome

Title	Proportion of Participants With Incidence of Hospitalization for Heart Failure
Description	To measure the incidence of hospitalization for heart failure among all subjects and among subjects who have a history of heart failure at baseline
Time Frame	Duration of study (168 weeks)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	All Subjects: Bexagliflozin Tablets, 20 mg	All Subjects: Placebo Tablets	Subjects With HF History: Bexagliflozin Tablets, 20 mg	Subjects With HF History: Placebo
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet This group includes all subjects who have received bexagliflozin in the study.	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator This group includes all subjects who have received placebo in the study.	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet This group includes subjects who reported a history of heart failure and randomized to the bexagliflozin arm.	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator This group includes subjects who reported a history of heart failure and randomized to the placebo arm.
Measure Participants	1133	567	302	151
Number (95% Confidence Interval) [Proportion of participants]	0.01 0%	0.02 0%	0.05 0%	0.09 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0803
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Logistic
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95% 0.33 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is calculated as the odds ratio of bexagliflozin over placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Subjects With HF History: Bexagliflozin Tablets, 20 mg, Subjects With HF History: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0272
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Logistic
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95% 0.22 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is calculated as the odds ratio of bexagliflozin over placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0757
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Cox
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95% 0.34 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio and p-value were estimated using Cox regression model for treatment comparison vs. placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Subjects With HF History: Bexagliflozin Tablets, 20 mg, Subjects With HF History: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0273
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Cox
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95% 0.23 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio and p-value were estimated using Cox regression model for treatment comparison vs. placebo.

Adverse Events

	Bexagliflozin Tablets, 20 mg		Placebo Tablets
Time Frame	Adverse event data were collected from the first dose to the last day of follow up (4 weeks after the End of Treatment visit, an average of 127 weeks)
Adverse Event Reporting Description

Arm/Group Title	Bexagliflozin Tablets, 20 mg		Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet		Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/1132 (3.4%)		26/567 (4.6%)
Serious Adverse Events
	Bexagliflozin Tablets, 20 mg		Placebo Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	373/1132 (33%)		208/567 (36.7%)
Blood and lymphatic system disorders
Anaemia	0/1132 (0%)	0	2/567 (0.4%)	2
Thrombocytopenia	2/1132 (0.2%)	2	0/567 (0%)	0
Haemorrhagic anaemia	1/1132 (0.1%)	1	0/567 (0%)	0
Iron deficiency anaemia	1/1132 (0.1%)	1	0/567 (0%)	0
Cardiac disorders
Angina unstable	31/1132 (2.7%)	39	19/567 (3.4%)	22
Acute myocardial infarction	31/1132 (2.7%)	33	14/567 (2.5%)	15
Cardiac failure congestive	18/1132 (1.6%)	21	15/567 (2.6%)	21
Cardiac failure	21/1132 (1.9%)	27	7/567 (1.2%)	9
Angina pectoris	16/1132 (1.4%)	20	11/567 (1.9%)	12
Coronary artery disease	21/1132 (1.9%)	21	6/567 (1.1%)	6
Atrial fibrillation	15/1132 (1.3%)	21	9/567 (1.6%)	17
Myocardial infarction	11/1132 (1%)	11	13/567 (2.3%)	13
Cardiac arrest	12/1132 (1.1%)	12	2/567 (0.4%)	2
Cardiac failure chronic	5/1132 (0.4%)	6	4/567 (0.7%)	4
Myocardial ischaemia	8/1132 (0.7%)	8	1/567 (0.2%)	1
Ventricular tachycardia	3/1132 (0.3%)	3	6/567 (1.1%)	7
Coronary artery occlusion	3/1132 (0.3%)	3	3/567 (0.5%)	3
Atrial flutter	3/1132 (0.3%)	3	2/567 (0.4%)	4
Coronary artery stenosis	3/1132 (0.3%)	3	2/567 (0.4%)	2
Arrhythmia	2/1132 (0.2%)	2	1/567 (0.2%)	1
Cardiac disorder	2/1132 (0.2%)	2	1/567 (0.2%)	1
Cardio-respiratory arrest	2/1132 (0.2%)	2	1/567 (0.2%)	1
Cardiopulmonary arrest	1/1132 (0.1%)	1	2/567 (0.4%)	2
Sinus node dysfunction	1/1132 (0.1%)	1	2/567 (0.4%)	2
Acute coronary syndrome	0/1132 (0%)	0	2/567 (0.4%)	2
Aortic valve stenosis	2/1132 (0.2%)	2	0/567 (0%)	0
Bradycardia	1/1132 (0.1%)	1	1/567 (0.2%)	1
Congestive cardiomyopathy	1/1132 (0.1%)	1	1/567 (0.2%)	1
Tachycardia	0/1132 (0%)	0	2/567 (0.4%)	2
Ventricular arrhythmia	2/1132 (0.2%)	2	0/567 (0%)	0
Anginal equivalent	1/1132 (0.1%)	1	0/567 (0%)	0
Aortic valve disease	1/1132 (0.1%)	1	0/567 (0%)	0
Aortic valve incompetence	0/1132 (0%)	0	1/567 (0.2%)	1
Atrioventricular block	1/1132 (0.1%)	1	0/567 (0%)	0
Cardiac asthma	1/1132 (0.1%)	1	0/567 (0%)	0
Cardiac failure acute	0/1132 (0%)	0	1/567 (0.2%)	1
Cardiogenic shock	1/1132 (0.1%)	1	0/567 (0%)	0
Cardiomyopathy	1/1132 (0.1%)	1	0/567 (0%)	0
Cardiorenal syndrome	1/1132 (0.1%)	1	0/567 (0%)	0
Heart valve incompetence	1/1132 (0.1%)	1	0/567 (0%)	0
Intracardiac thrombus	1/1132 (0.1%)	3	0/567 (0%)	0
Ischaemic cardiomyopathy	1/1132 (0.1%)	1	0/567 (0%)	0
Left ventricular failure	0/1132 (0%)	0	1/567 (0.2%)	1
Mitral valve incompetence	0/1132 (0%)	0	1/567 (0.2%)	1
Pericardial effusion	1/1132 (0.1%)	1	0/567 (0%)	0
Sinus tachycardia	1/1132 (0.1%)	1	0/567 (0%)	0
Ventricular fibrillation	0/1132 (0%)	0	1/567 (0.2%)	1
Congenital, familial and genetic disorders
Hydrocele	2/1132 (0.2%)	2	0/567 (0%)	0
Atrial septal defect	1/1132 (0.1%)	1	0/567 (0%)	0
Phimosis	1/1132 (0.1%)	1	0/567 (0%)	0
Ear and labyrinth disorders
Vertigo	2/1132 (0.2%)	2	0/567 (0%)	0
Vertigo positional	1/1132 (0.1%)	1	0/567 (0%)	0
Eye disorders
Cataract	3/1132 (0.3%)	4	1/567 (0.2%)	1
Corneal lesion	0/1132 (0%)	0	1/567 (0.2%)	1
Glaucoma	1/1132 (0.1%)	1	0/567 (0%)	0
Keratopathy	1/1132 (0.1%)	1	0/567 (0%)	0
Lens dislocation	0/1132 (0%)	0	1/567 (0.2%)	1
Retinal vein thrombosis	1/1132 (0.1%)	1	0/567 (0%)	0
Gastrointestinal disorders
Gastrointestinal haemorrhage	2/1132 (0.2%)	2	4/567 (0.7%)	4
Diarrhoea	4/1132 (0.4%)	4	0/567 (0%)	0
Colitis	3/1132 (0.3%)	3	0/567 (0%)	0
Diverticulum	1/1132 (0.1%)	1	2/567 (0.4%)	2
Gastric ulcer	1/1132 (0.1%)	1	2/567 (0.4%)	2
Gastrooesophageal reflux disease	1/1132 (0.1%)	1	2/567 (0.4%)	2
Small intestinal obstruction	1/1132 (0.1%)	1	2/567 (0.4%)	2
Umbilical hernia	2/1132 (0.2%)	2	1/567 (0.2%)	1
Upper gastrointestinal haemorrhage	2/1132 (0.2%)	2	1/567 (0.2%)	1
Large intestine polyp	1/1132 (0.1%)	1	1/567 (0.2%)	1
Abdominal pain	1/1132 (0.1%)	1	0/567 (0%)	0
Abdominal pain upper	1/1132 (0.1%)	1	0/567 (0%)	0
Anal fistula	0/1132 (0%)	0	1/567 (0.2%)	1
Barret's oesophagus	1/1132 (0.1%)	2	0/567 (0%)	0
Colitis ischaemic	0/1132 (0%)	0	1/567 (0.2%)	2
Crohn's disease	1/1132 (0.1%)	1	0/567 (0%)	0
Duodenal ulcer haemorrhage	1/1132 (0.1%)	1	0/567 (0%)	0
Enterocutaneous fistula	1/1132 (0.1%)	1	0/567 (0%)	0
Fecal incontinence	0/1132 (0%)	0	1/567 (0.2%)	1
Gastric polyps	0/1132 (0%)	0	1/567 (0.2%)	1
Gastrointestinal polyp haemorrhage	0/1132 (0%)	0	1/567 (0.2%)	1
Hiatus hernia	1/1132 (0.1%)	1	0/567 (0%)	0
Incarcerated inguinal hernia	1/1132 (0.1%)	1	0/567 (0%)	0
Inguinal hernia	0/1132 (0%)	0	1/567 (0.2%)	1
Intra-abdominal haematoma	0/1132 (0%)	0	1/567 (0.2%)	1
Mesenteric vein thrombosis	1/1132 (0.1%)	1	0/567 (0%)	0
Pancreatitis acute	0/1132 (0%)	0	1/567 (0.2%)	1
Rectal perforation	1/1132 (0.1%)	1	0/567 (0%)	0
Rectal polyp	1/1132 (0.1%)	1	0/567 (0%)	0
Subileus	0/1132 (0%)	0	1/567 (0.2%)	1
General disorders
Non-cardiac chest pain	6/1132 (0.5%)	7	5/567 (0.9%)	5
Chest pain	6/1132 (0.5%)	7	3/567 (0.5%)	3
Necrosis	3/1132 (0.3%)	3	1/567 (0.2%)	1
Death	2/1132 (0.2%)	2	0/567 (0%)	0
Device malfunction	1/1132 (0.1%)	1	1/567 (0.2%)	1
Oedema peripheral	2/1132 (0.2%)	2	0/567 (0%)	0
Adverse drug reaction	1/1132 (0.1%)	1	0/567 (0%)	0
Asthenia	1/1132 (0.1%)	1	0/567 (0%)	0
Chest discomfort	1/1132 (0.1%)	1	0/567 (0%)	0
Complication associated with device	0/1132 (0%)	0	1/567 (0.2%)	1
Impaired healing	1/1132 (0.1%)	1	0/567 (0%)	0
Medical device complication	1/1132 (0.1%)	1	0/567 (0%)	0
Sudden cardiac death	1/1132 (0.1%)	1	0/567 (0%)	0
Hepatobiliary disorders
Cholecystitis	2/1132 (0.2%)	2	1/567 (0.2%)	1
Cholangitis	1/1132 (0.1%)	1	1/567 (0.2%)	1
Cholecystitis acute	1/1132 (0.1%)	1	1/567 (0.2%)	1
Cholelithiasis	0/1132 (0%)	0	2/567 (0.4%)	2
Bile duct stone	1/1132 (0.1%)	1	0/567 (0%)	0
Cholangitis acute	1/1132 (0.1%)	1	0/567 (0%)	0
Hepatic cirrhosis	1/1132 (0.1%)	1	0/567 (0%)	0
Infections and infestations
Pneumonia	11/1132 (1%)	11	10/567 (1.8%)	10
Cellulitis	9/1132 (0.8%)	11	2/567 (0.4%)	2
Osteomyelitis	10/1132 (0.9%)	13	1/567 (0.2%)	1
Sepsis	9/1132 (0.8%)	9	1/567 (0.2%)	1
Urinary tract infection	6/1132 (0.5%)	6	3/567 (0.5%)	3
Gangrene	4/1132 (0.4%)	5	3/567 (0.5%)	4
Diverticulitis	3/1132 (0.3%)	3	3/567 (0.5%)	3
Appendicitis	2/1132 (0.2%)	2	2/567 (0.4%)	2
Localised infection	4/1132 (0.4%)	4	0/567 (0%)	0
Pyelonephritis	3/1132 (0.3%)	3	1/567 (0.2%)	1
Endocarditis	3/1132 (0.3%)	3	0/567 (0%)	0
Influenza	1/1132 (0.1%)	1	2/567 (0.4%)	2
Septic shock	3/1132 (0.3%)	3	0/567 (0%)	0
Urosepsis	2/1132 (0.2%)	2	1/567 (0.2%)	1
Abdominal abscess	2/1132 (0.2%)	2	0/567 (0%)	0
Bacteraemia	1/1132 (0.1%)	1	1/567 (0.2%)	1
Erysipelas	2/1132 (0.2%)	2	0/567 (0%)	0
Gastroenteritis	1/1132 (0.1%)	1	1/567 (0.2%)	1
Gastroenteritis viral	2/1132 (0.2%)	2	0/567 (0%)	0
Wound infection	1/1132 (0.1%)	1	1/567 (0.2%)	1
Abdominal wall abscess	1/1132 (0.1%)	1	0/567 (0%)	0
Abscess limb	1/1132 (0.1%)	1	0/567 (0%)	0
Atypical pneumonia	1/1132 (0.1%)	1	0/567 (0%)	0
Biliary tract infection	1/1132 (0.1%)	1	0/567 (0%)	0
Bronchitis	0/1132 (0%)	0	1/567 (0.2%)	1
Bursitis infective	0/1132 (0%)	0	1/567 (0.2%)	1
Chronic sinusitis	1/1132 (0.1%)	1	0/567 (0%)	0
Device related infection	1/1132 (0.1%)	1	0/567 (0%)	0
Diabetic foot infection	0/1132 (0%)	0	1/567 (0.2%)	1
Ear infection	0/1132 (0%)	0	1/567 (0.2%)	1
Emphysematous cholecystitis	1/1132 (0.1%)	1	0/567 (0%)	0
Enterococcal bacteraemia	0/1132 (0%)	0	1/567 (0.2%)	1
Gas gangrene	1/1132 (0.1%)	1	0/567 (0%)	0
Gastroenteritis salmonella	0/1132 (0%)	0	1/567 (0.2%)	1
Hepatitis B	1/1132 (0.1%)	1	0/567 (0%)	0
Infected skin ulcer	1/1132 (0.1%)	1	0/567 (0%)	0
Medical device site joint infection	1/1132 (0.1%)	1	0/567 (0%)	0
Myelitis	1/1132 (0.1%)	1	0/567 (0%)	0
Oesophageal candidiasis	0/1132 (0%)	0	1/567 (0.2%)	1
Peritonitis	1/1132 (0.1%)	1	0/567 (0%)	0
Pneumonia legionella	1/1132 (0.1%)	1	0/567 (0%)	0
Pneumonia streptococcal	0/1132 (0%)	0	1/567 (0.2%)	1
Postoperative wound infection	0/1132 (0%)	0	1/567 (0.2%)	1
Pyelonephritis acute	0/1132 (0%)	0	1/567 (0.2%)	1
Scrotal abscess	1/1132 (0.1%)	1	0/567 (0%)	0
Skin infection	1/1132 (0.1%)	1	0/567 (0%)	0
Subcutaneous abscess	0/1132 (0%)	0	1/567 (0.2%)	1
Viral infection	1/1132 (0.1%)	1	0/567 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/1132 (0.1%)	1	2/567 (0.4%)	2
Femur fracture	3/1132 (0.3%)	3	0/567 (0%)	0
Hip fracture	2/1132 (0.2%)	2	1/567 (0.2%)	1
Patella fracture	3/1132 (0.3%)	3	0/567 (0%)	0
Concussion	2/1132 (0.2%)	2	0/567 (0%)	0
Foot fracture	2/1132 (0.2%)	2	0/567 (0%)	0
Joint injury	0/1132 (0%)	0	2/567 (0.4%)	2
Rib fracture	2/1132 (0.2%)	2	0/567 (0%)	0
Spinal fracture	2/1132 (0.2%)	2	0/567 (0%)	0
Anastomotic ulcer	0/1132 (0%)	0	1/567 (0.2%)	1
Compression fracture	0/1132 (0%)	0	1/567 (0.2%)	1
Craniocerebral injury	1/1132 (0.1%)	1	0/567 (0%)	0
Fall	0/1132 (0%)	0	1/567 (0.2%)	1
Fibula fracture	1/1132 (0.1%)	1	0/567 (0%)	0
Humerus fracture	1/1132 (0.1%)	1	0/567 (0%)	0
Laceration	1/1132 (0.1%)	1	0/567 (0%)	0
Ligament rupture	0/1132 (0%)	0	1/567 (0.2%)	1
Limb injury	1/1132 (0.1%)	1	0/567 (0%)	0
Lower limb fracture	1/1132 (0.1%)	1	0/567 (0%)	0
Meniscus injury	1/1132 (0.1%)	1	0/567 (0%)	0
Pneumoconiosis	0/1132 (0%)	0	1/567 (0.2%)	1
Post procedural complication	1/1132 (0.1%)	1	0/567 (0%)	0
Post procedural haemorrhage	1/1132 (0.1%)	1	0/567 (0%)	0
Procedural pain	1/1132 (0.1%)	1	0/567 (0%)	0
Pulmonary contusion	0/1132 (0%)	0	1/567 (0.2%)	1
Seroma	0/1132 (0%)	0	1/567 (0.2%)	1
Subdural haematoma	1/1132 (0.1%)	1	0/567 (0%)	0
Subdural haemorrhage	0/1132 (0%)	0	1/567 (0.2%)	1
Vascular pseudoaneurysm	1/1132 (0.1%)	1	0/567 (0%)	0
Investigations
Troponin increased	2/1132 (0.2%)	2	0/567 (0%)	0
Blood creatinine increased	1/1132 (0.1%)	1	0/567 (0%)	0
Metabolism and nutrition disorders
Hypoglycaemia	14/1132 (1.2%)	15	8/567 (1.4%)	10
Dehydration	1/1132 (0.1%)	1	3/567 (0.5%)	3
Hyperkalaemia	3/1132 (0.3%)	3	1/567 (0.2%)	1
Diabetic ketoacidosis	0/1132 (0%)	0	3/567 (0.5%)	4
Gout	1/1132 (0.1%)	1	2/567 (0.4%)	2
Diabetes mellitus inadequate control	2/1132 (0.2%)	2	0/567 (0%)	0
Hyperglycaemia	0/1132 (0%)	0	2/567 (0.4%)	2
Hypokalaemia	2/1132 (0.2%)	2	0/567 (0%)	0
Metabolic acidosis	2/1132 (0.2%)	2	0/567 (0%)	0
Diabetic complication	1/1132 (0.1%)	1	0/567 (0%)	0
Latent autoimmune diabetes in adults	0/1132 (0%)	0	1/567 (0.2%)	1
Obesity	1/1132 (0.1%)	1	0/567 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	15/1132 (1.3%)	17	4/567 (0.7%)	4
Musculoskeletal chest pain	2/1132 (0.2%)	2	2/567 (0.4%)	2
Arthritis	2/1132 (0.2%)	2	1/567 (0.2%)	1
Intervertebral disc protrusion	2/1132 (0.2%)	2	1/567 (0.2%)	1
Spinal column stenosis	3/1132 (0.3%)	3	0/567 (0%)	0
Lumbar spinal stenosis	1/1132 (0.1%)	1	1/567 (0.2%)	1
Musculoskeletal pain	1/1132 (0.1%)	1	1/567 (0.2%)	1
Arthralgia	1/1132 (0.1%)	1	0/567 (0%)	0
Arthropathy	1/1132 (0.1%)	1	0/567 (0%)	0
Bursitis	1/1132 (0.1%)	1	0/567 (0%)	0
Cervical spinal stenosis	1/1132 (0.1%)	1	0/567 (0%)	0
Dupuytren's contracture	1/1132 (0.1%)	1	0/567 (0%)	0
Immunoglobulin G4 related sclerosing disease	1/1132 (0.1%)	1	0/567 (0%)	0
Intervertebral disc disorder	1/1132 (0.1%)	1	0/567 (0%)	0
Joint instability	1/1132 (0.1%)	1	0/567 (0%)	0
Muscle spasms	0/1132 (0%)	0	1/567 (0.2%)	1
Neuropathic arthropathy	1/1132 (0.1%)	1	0/567 (0%)	0
Osteochondrosis	0/1132 (0%)	0	1/567 (0.2%)	1
Scoliosis	1/1132 (0.1%)	1	0/567 (0%)	0
Spinal osteoarthritis	0/1132 (0%)	0	1/567 (0.2%)	1
Tenosynovitis	0/1132 (0%)	0	1/567 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma	0/1132 (0%)	0	3/567 (0.5%)	3
Prostate cancer	2/1132 (0.2%)	2	1/567 (0.2%)	1
Transitional cell carcinoma	3/1132 (0.3%)	3	0/567 (0%)	0
Invasive ductal breast carcinoma	1/1132 (0.1%)	1	1/567 (0.2%)	1
Lipoma	1/1132 (0.1%)	1	1/567 (0.2%)	1
Lung adenocarcinoma	2/1132 (0.2%)	2	0/567 (0%)	0
Lung neoplasm malignant	2/1132 (0.2%)	2	0/567 (0%)	0
Malignant melanoma	1/1132 (0.1%)	1	1/567 (0.2%)	1
Adenocarcinoma gastric	1/1132 (0.1%)	1	0/567 (0%)	0
Adenocarcinoma of colon	0/1132 (0%)	0	1/567 (0.2%)	1
Adenocarcinoma pancreas	1/1132 (0.1%)	1	0/567 (0%)	0
Adrenal adenoma	0/1132 (0%)	0	1/567 (0.2%)	1
B-cell lymphoma	1/1132 (0.1%)	1	0/567 (0%)	0
Biliary cancer metastatic	1/1132 (0.1%)	1	0/567 (0%)	0
Carcinoid tumour of the appendix	1/1132 (0.1%)	1	0/567 (0%)	0
Cervix carcinoma	0/1132 (0%)	0	1/567 (0.2%)	1
Colon cancer	0/1132 (0%)	0	1/567 (0.2%)	1
Colon cancer recurrent	0/1132 (0%)	0	1/567 (0.2%)	1
Colorectal adenocarcinoma	0/1132 (0%)	0	1/567 (0.2%)	1
Endometrial adenocarcinoma	1/1132 (0.1%)	1	0/567 (0%)	0
Gastric adenoma	1/1132 (0.1%)	1	0/567 (0%)	0
Hepatic neoplasm	0/1132 (0%)	0	1/567 (0.2%)	1
Hepatocellular carcinoma	1/1132 (0.1%)	1	0/567 (0%)	0
Invasive papillary breast carcinoma	1/1132 (0.1%)	1	0/567 (0%)	0
Malignant neoplasm of ampulla of Vater	0/1132 (0%)	0	1/567 (0.2%)	1
Metastatic renal cell carcinoma	0/1132 (0%)	0	1/567 (0.2%)	1
Myelodysplastic syndrome	1/1132 (0.1%)	1	0/567 (0%)	0
Myeloproliferative disorder	1/1132 (0.1%)	1	0/567 (0%)	0
Non-small cell lung cancer	0/1132 (0%)	0	1/567 (0.2%)	1
Ovarian cancer	0/1132 (0%)	0	1/567 (0.2%)	1
Papillary cystadenoma lymphomatosum	0/1132 (0%)	0	1/567 (0.2%)	1
Pituitary tumour benign	0/1132 (0%)	0	1/567 (0.2%)	1
Polycythaemia vera	1/1132 (0.1%)	1	0/567 (0%)	0
Renal cancer	1/1132 (0.1%)	1	0/567 (0%)	0
Renal cancer metastatic	1/1132 (0.1%)	1	0/567 (0%)	0
Renal cell carcinoma	1/1132 (0.1%)	1	0/567 (0%)	0
Squamous cell carcinoma of lung	1/1132 (0.1%)	1	0/567 (0%)	0
Uterine leiomyoma	0/1132 (0%)	0	1/567 (0.2%)	1
Nervous system disorders
Cerebrovascular accident	15/1132 (1.3%)	15	7/567 (1.2%)	7
Ischaemic stroke	10/1132 (0.9%)	11	4/567 (0.7%)	4
Transient ischaemic attack	6/1132 (0.5%)	7	5/567 (0.9%)	6
Carotid artery stenosis	7/1132 (0.6%)	9	3/567 (0.5%)	3
Syncope	4/1132 (0.4%)	4	4/567 (0.7%)	4
Subarachnoid haemorrhage	3/1132 (0.3%)	3	0/567 (0%)	0
Carpal tunnel syndrome	2/1132 (0.2%)	2	0/567 (0%)	0
Cerebral infarction	1/1132 (0.1%)	1	1/567 (0.2%)	1
Dizziness	1/1132 (0.1%)	1	1/567 (0.2%)	1
Presyncope	2/1132 (0.2%)	2	0/567 (0%)	0
Sciatica	1/1132 (0.1%)	1	1/567 (0.2%)	1
Aphasia	1/1132 (0.1%)	1	0/567 (0%)	0
Brain stem infarction	0/1132 (0%)	0	1/567 (0.2%)	1
Central nervous system haemorrhage	0/1132 (0%)	0	1/567 (0.2%)	1
Cerebral artery stenosis	1/1132 (0.1%)	1	0/567 (0%)	0
Cerebral artery thrombosis	1/1132 (0.1%)	1	0/567 (0%)	0
Cervical myelopathy	0/1132 (0%)	0	1/567 (0.2%)	1
Cervical radiculopathy	1/1132 (0.1%)	1	0/567 (0%)	0
Encephalopathy	0/1132 (0%)	0	1/567 (0.2%)	1
Epilepsy	1/1132 (0.1%)	1	0/567 (0%)	0
Haemorrhage intracranial	1/1132 (0.1%)	2	0/567 (0%)	0
Headache	1/1132 (0.1%)	1	0/567 (0%)	0
Hemiparesis	1/1132 (0.1%)	1	0/567 (0%)	0
Hypoaesthesia	0/1132 (0%)	0	1/567 (0.2%)	1
Miller Fisher syndrome	0/1132 (0%)	0	1/567 (0.2%)	1
Myasthenia gravis	1/1132 (0.1%)	1	0/567 (0%)	0
Neurological symptom	1/1132 (0.1%)	1	0/567 (0%)	0
Normal pressure hydrocephalus	0/1132 (0%)	0	1/567 (0.2%)	1
Paraesthesia	0/1132 (0%)	0	1/567 (0.2%)	1
Parkinson's disease	1/1132 (0.1%)	1	0/567 (0%)	0
Polyneuropathy	1/1132 (0.1%)	1	0/567 (0%)	0
Radiculopathy	1/1132 (0.1%)	1	0/567 (0%)	0
Thalamic infarction	1/1132 (0.1%)	1	0/567 (0%)	0
Psychiatric disorders
Bipolar I disorder	0/1132 (0%)	0	1/567 (0.2%)	1
Delirium	1/1132 (0.1%)	1	0/567 (0%)	0
Suicidal ideation	1/1132 (0.1%)	1	0/567 (0%)	0
Suicide attempt	1/1132 (0.1%)	1	0/567 (0%)	0
Renal and urinary disorders
Acute kidney injury	9/1132 (0.8%)	10	4/567 (0.7%)	4
Nephrolithiasis	3/1132 (0.3%)	4	2/567 (0.4%)	2
Calculus ureteric	2/1132 (0.2%)	2	0/567 (0%)	0
Calculus urinary	1/1132 (0.1%)	1	1/567 (0.2%)	1
Chronic kidney disease	1/1132 (0.1%)	1	1/567 (0.2%)	1
Haematuria	1/1132 (0.1%)	1	0/567 (0%)	0
Obstructive uropathy	0/1132 (0%)	0	1/567 (0.2%)	1
Renal colic	1/1132 (0.1%)	1	0/567 (0%)	0
Urinary retention	1/1132 (0.1%)	1	0/567 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	3/1132 (0.3%)	3	1/567 (0.2%)	1
Erectile dysfunction	1/1132 (0.1%)	1	1/567 (0.2%)	1
Cervix disorder	1/1132 (0.1%)	1	0/567 (0%)	0
Oedema genital	1/1132 (0.1%)	2	0/567 (0%)	0
Prostatism	1/1132 (0.1%)	1	0/567 (0%)	0
Prostatitis	0/1132 (0%)	0	1/567 (0.2%)	1
Uterine prolapse	1/1132 (0.1%)	1	0/567 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	10/1132 (0.9%)	11	3/567 (0.5%)	6
Respiratory failure	9/1132 (0.8%)	10	3/567 (0.5%)	4
Acute respiratory failure	6/1132 (0.5%)	6	1/567 (0.2%)	1
Pleural effusion	4/1132 (0.4%)	4	0/567 (0%)	0
Acute pulmonary edema	2/1132 (0.2%)	2	0/567 (0%)	0
Pulmonary oedema	0/1132 (0%)	0	2/567 (0.4%)	2
Aspiration	0/1132 (0%)	0	1/567 (0.2%)	1
Asthma	1/1132 (0.1%)	1	0/567 (0%)	0
Dyspnoea	1/1132 (0.1%)	1	0/567 (0%)	0
Epistaxis	1/1132 (0.1%)	1	0/567 (0%)	0
Haemothorax	1/1132 (0.1%)	1	0/567 (0%)	0
Hypoxia	1/1132 (0.1%)	1	0/567 (0%)	0
Lung disorder	0/1132 (0%)	0	1/567 (0.2%)	1
Nasal polyps	1/1132 (0.1%)	1	0/567 (0%)	0
Pleurisy	1/1132 (0.1%)	1	0/567 (0%)	0
Pneumothorax	1/1132 (0.1%)	1	0/567 (0%)	0
Respiratory distress	1/1132 (0.1%)	1	0/567 (0%)	0
Sleep apnoea syndrome	0/1132 (0%)	0	1/567 (0.2%)	1
Vocal cord polyp	0/1132 (0%)	0	1/567 (0.2%)	1
Skin and subcutaneous tissue disorders
Skin ulcer	2/1132 (0.2%)	2	3/567 (0.5%)	6
Diabetic foot	3/1132 (0.3%)	3	1/567 (0.2%)	1
Dermatitis contact	1/1132 (0.1%)	1	0/567 (0%)	0
Excessive granulation tissue	1/1132 (0.1%)	1	0/567 (0%)	0
Surgical and medical procedures
Cardiac pacemaker battery replacement	1/1132 (0.1%)	1	0/567 (0%)	0
Cardiac pacemaker replacement	0/1132 (0%)	0	1/567 (0.2%)	1
Implantable defibrillator insertion	1/1132 (0.1%)	1	0/567 (0%)	0
Prophylaxis	0/1132 (0%)	0	1/567 (0.2%)	1
Vitrectomy	1/1132 (0.1%)	1	0/567 (0%)	0
Vascular disorders
Peripheral ischaemia	11/1132 (1%)	12	7/567 (1.2%)	8
Peripheral arterial occlusive disease	8/1132 (0.7%)	11	6/567 (1.1%)	8
Hypotension	5/1132 (0.4%)	5	1/567 (0.2%)	1
Hypertension	2/1132 (0.2%)	2	2/567 (0.4%)	2
Orthostatic hypotension	3/1132 (0.3%)	3	1/567 (0.2%)	1
Arteriosclerosis	2/1132 (0.2%)	2	1/567 (0.2%)	1
Femoral artery occlusion	3/1132 (0.3%)	3	0/567 (0%)	0
Hypertensive crisis	1/1132 (0.1%)	1	2/567 (0.4%)	2
Intermittent claudication	1/1132 (0.1%)	3	2/567 (0.4%)	2
Peripheral vascular disorder	1/1132 (0.1%)	1	2/567 (0.4%)	2
Deep vein thrombosis	1/1132 (0.1%)	1	1/567 (0.2%)	1
Peripheral artery stenosis	2/1132 (0.2%)	3	0/567 (0%)	0
Peripheral artery thrombosis	1/1132 (0.1%)	1	1/567 (0.2%)	1
Aortic stenosis	1/1132 (0.1%)	1	0/567 (0%)	0
Hypertensive emergency	1/1132 (0.1%)	1	0/567 (0%)	0
Iliac artery occlusion	1/1132 (0.1%)	1	0/567 (0%)	0
Leriche syndrome	1/1132 (0.1%)	1	0/567 (0%)	0
Lymphoedema	0/1132 (0%)	0	1/567 (0.2%)	2
Necrosis ischaemic	0/1132 (0%)	0	1/567 (0.2%)	1
Subclavian vein thrombosis	0/1132 (0%)	0	1/567 (0.2%)	1
Varicose vein	1/1132 (0.1%)	1	0/567 (0%)	0
Venous thrombosis	0/1132 (0%)	0	1/567 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Bexagliflozin Tablets, 20 mg		Placebo Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	739/1132 (65.3%)		386/567 (68.1%)
Gastrointestinal disorders
Diarrhoea	72/1132 (6.4%)	90	31/567 (5.5%)	40
Nausea	54/1132 (4.8%)	64	37/567 (6.5%)	45
Infections and infestations
Bronchitis	52/1132 (4.6%)	65	34/567 (6%)	40
Nasopharyngitis	96/1132 (8.5%)	115	39/567 (6.9%)	46
Upper respiratory tract infection	112/1132 (9.9%)	147	53/567 (9.3%)	82
Urinary tract infection	128/1132 (11.3%)	190	60/567 (10.6%)	96
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	49/1132 (4.3%)	53	29/567 (5.1%)	37
Hyperglycaemia	68/1132 (6%)	181	41/567 (7.2%)	80
Hypoglycaemia	475/1132 (42%)	3743	246/567 (43.4%)	1857
Musculoskeletal and connective tissue disorders
Arthralgia	49/1132 (4.3%)	56	30/567 (5.3%)	37
Back pain	66/1132 (5.8%)	72	33/567 (5.8%)	36
Vascular disorders
Hypertension	45/1132 (4%)	46	36/567 (6.3%)	38

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

There IS 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.

Results Point of Contact

Name/Title	Albert Collinson
Organization	Theracos Sub, LLC
Phone	(508) 630-2129
Email	acollinson@theracos.com

Responsible Party:

Theracos

ClinicalTrials.gov Identifier:

NCT02558296

Other Study ID Numbers:

THR-1442-C-476

First Posted:

Sep 23, 2015

Last Update Posted:

Jul 14, 2021

Last Verified:

Jul 1, 2021

BEST: Bexagliflozin Efficacy and Safety Trial

Study Details

Study Description

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Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Other Outcome Measures

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Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

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Sponsors and Collaborators

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Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Statistical Analysis 7

Statistical Analysis 8

Statistical Analysis 9

Statistical Analysis 10

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Statistical Analysis 7

Statistical Analysis 8

Statistical Analysis 9

Statistical Analysis 10

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Adverse Events

All Cause Mortality

Serious Adverse Events

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Limitations/Caveats

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Results Point of Contact