Efficacy and Safety of BI 10773 in Combination With Insulin in Patients With Type 2 Diabetes

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01011868
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 494
• Locations: 99
• Arms: 3
• Patients Per Site: 5

Study Details

Study Description

Brief Summary

The objective of the current study is to investigate the efficacy, safety and tolerability of BI 10773 at two different doses compared to placebo during long term treatment (78 weeks) in combination with basal insulin in patients with type 2 diabetes mellitus with insufficient glycaemic control.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: BI 10773 placebo; Drug: BI 10773 low dose; Drug: BI 10773 high dose; Drug: BI 10773 placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 494 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Phase IIb, Randomized, Double-blind, Placebo-controlled, Parallel Group, Safety and Efficacy Study of BI 10773 (10 mg and 25 mg) Administered Orally, Once Daily Over 78 Weeks in Type 2 Diabetic Patients Receiving Treatment With Basal Insulin (Glargine, Detemir, or NPH Insulin Only) With or Without Concomitant Metformin and/or Sulfonylurea Therapy and Insufficient Glycemic Control
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: May 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 10773 low dose Patients receive BI 10773 low dose daily	Drug: BI 10773 low dose; BI 10773 low dose
Experimental: BI 10773 high dose Patients receive BI 10773 high dose daily	Drug: BI 10773 placebo; BI 10773 placebo; Drug: BI 10773 high dose; BI 10773 high dose
Placebo Comparator: placebo Patients receive placebo to match BI 10773 daily	Drug: BI 10773 placebo; BI 10773 placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) After 18 Weeks of Treatment [Baseline and 18 weeks]

   Change from baseline in Glycosylated haemoglobin A1c (HbA1c) after 18 weeks of treatment

Secondary Outcome Measures

1. Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5%) After 18, 54 and 78 Weeks of Treatment [Baseline and 18, 54 and 78 weeks]

   Patients that had a reduction in HbA1c of at least 0.5% from baseline to 18, 54 and 78 weeks of treatment

2. Change From Baseline in Fasting Plasma Glucose (FPG) After 18, 54 and 78 Weeks of Treatment [Baseline, 18, 54 and 78 weeks]

   Change from baseline in fasting plasma glucose (FPG) after 18, 54 and 78 weeks of treatment

3. Percent Change From Baseline in Fasting Plasma Glucose (FPG) After 18, 54 and 78 Weeks of Treatment [Baseline, 18, 54 and 78 weeks]

   Percent change from baseline in fasting plasma glucose (FPG) after 18, 54 and 78 weeks of treatment

4. Change From Baseline in Basal Insulin Dose/Day After 54 and 78 Weeks of Treatment [Baseline, 54 and 78 weeks]

   Change from baseline in basal insulin dose/day after 54 and 78 weeks of treatment

5. Change From Baseline in Body Weight After 18, 54 and 78 Weeks of Treatment [Baseline, 18, 54, 78 weeks]

   Change from baseline in body weight after 18, 54 and 78 weeks of treatment

6. Change From Baseline in Body Weight at Follow-up [Baseline and 82 weeks]

   Change from baseline in body weight at follow up (82 weeks)

7. Change From Baseline in HbA1c After 54 and 78 Weeks of Treatment [Baseline, 54 and 78 weeks]

   Change from baseline in HbA1c after 54 and 78 weeks of treatment

8. The Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <7.0% After 18, 54, and 78 Weeks of Treatment [Baseline, 18, 54 and 78 weeks]

   The occurrence of treat to target efficacy response, that is an HbA1c under treatment of <7.0% After 18, 54, and 78 weeks of treatment

Other Outcome Measures

1. Confirmed Hypoglycemic Events [During the course of the study (82 weeks)]

   Confirmed hypoglycemic events refer to all hypoglycemic events that had a glucose value ≤70 ml/dL or where assistance was required. Symptomatic hypoglycemic events were to be reported as adverse events. Investigator-defined hypoglycaemia adverse events include all events that investigator marked as 'Hypoglycaemic event' in CRFs, regardless of the reported term or blood glucose value. It may include hypoglycemia itself as reported term or any other symptoms that that investigator may have attributed to hypoglycemia (e.g. dizziness, hyperhidrosis, and asthenia).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation

2. Male and female patients with a diagnosis of Type 2 Diabetes Mellitus treated with a stable dose of basal insulin with or without concomitant metformin and / or sulfonylurea.

3. Glycosylated hemoglobin A1c (Type A, subtype 1c) of >7.0% and < or = 10% at Visit 1 (screening)

4. Suitability for trial participation according to investigator's judgment (evaluating all alternative treatment options and in consideration of the patient completing the study)

5. Age > or =18 years at Visit 1 (screening)

6. BMI < or = 45 kg/m2 (Body Mass Index) at Visit 1 (screening)

Exclusion criteria:

1. Patients with poorly controlled hyperglycemia

2. Frequent (at the discretion of the investigator) episodes of hypoglycemic events on basal insulin therapy

3. MI, stroke, or TIA within 3 months prior to obtaining informed consent

4. Impaired hepatic or renal function; gastric surgery; cancer within the last 5 years; blood dyscrasias

5. Treatment with other anti-diabetics, anti-obesity medications, steroids or thyroid hormones, participation in another trial with an investigational drug 7. Pre-menopausal women on insufficient birth control 8. Alcohol or drug abuse

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1245.33.01014 Boehringer Ingelheim Investigational Site	Birmingham	Alabama	United States
2	1245.33.01047 Boehringer Ingelheim Investigational Site	Phoenix	Arizona	United States
3	1245.33.01060 Boehringer Ingelheim Investigational Site	Fresno	California	United States
4	1245.33.01013 Boehringer Ingelheim Investigational Site	Los Angeles	California	United States
5	1245.33.01008 Boehringer Ingelheim Investigational Site	Los Gatos	California	United States
6	1245.33.01019 Boehringer Ingelheim Investigational Site	National City	California	United States
7	1245.33.01055 Boehringer Ingelheim Investigational Site	Paramount	California	United States
8	1245.33.01012 Boehringer Ingelheim Investigational Site	Santa Ana	California	United States
9	1245.33.01054 Boehringer Ingelheim Investigational Site	Denver	Colorado	United States
10	1245.33.01046 Boehringer Ingelheim Investigational Site	Bradednton	Florida	United States
11	1245.33.01050 Boehringer Ingelheim Investigational Site	Brooksville	Florida	United States
12	1245.33.01059 Boehringer Ingelheim Investigational Site	Chiefland	Florida	United States
13	1245.33.01028 Boehringer Ingelheim Investigational Site	Clearwater	Florida	United States
14	1245.33.01029 Boehringer Ingelheim Investigational Site	Fleming Island	Florida	United States
15	1245.33.01048 Boehringer Ingelheim Investigational Site	Hollywood	Florida	United States
16	1245.33.01033 Boehringer Ingelheim Investigational Site	New Port Richey	Florida	United States
17	1245.33.01027 Boehringer Ingelheim Investigational Site	Atlanta	Georgia	United States
18	1245.33.01040 Boehringer Ingelheim Investigational Site	Decatur	Georgia	United States
19	1245.33.01062 Boehringer Ingelheim Investigational Site	Lawrenceville	Georgia	United States
20	1245.33.01020 Boehringer Ingelheim Investigational Site	Chicago	Illinois	United States
21	1245.33.01044 Boehringer Ingelheim Investigational Site	Chicago	Illinois	United States
22	1245.33.01024 Boehringer Ingelheim Investigational Site	Des Moines	Iowa	United States
23	1245.33.01022 Boehringer Ingelheim Investigational Site	St. Louis	Maryland	United States
24	1245.33.01056 Boehringer Ingelheim Investigational Site	Olive Branch	Mississippi	United States
25	1245.33.01032 Boehringer Ingelheim Investigational Site	Kansas City	Missouri	United States
26	1245.33.01017 Boehringer Ingelheim Investigational Site	Omaha	Nebraska	United States
27	1245.33.01043 Boehringer Ingelheim Investigational Site	Las Vegas	Nevada	United States
28	1245.33.01051 Boehringer Ingelheim Investigational Site	New Hartford	New York	United States
29	1245.33.01007 Boehringer Ingelheim Investigational Site	Greensboro	North Carolina	United States
30	1245.33.01003 Boehringer Ingelheim Investigational Site	Jacksonville	North Carolina	United States
31	1245.33.01016 Boehringer Ingelheim Investigational Site	Salisbury	North Carolina	United States
32	1245.33.01005 Boehringer Ingelheim Investigational Site	Statesville	North Carolina	United States
33	1245.33.01038 Boehringer Ingelheim Investigational Site	Wilmington	North Carolina	United States
34	1245.33.01026 Boehringer Ingelheim Investigational Site	Winston-Salem	North Carolina	United States
35	1245.33.01025 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio	United States
36	1245.33.01001 Boehringer Ingelheim Investigational Site	Columbus	Ohio	United States
37	1245.33.01031 Boehringer Ingelheim Investigational Site	Tulsa	Oklahoma	United States
38	1245.33.01045 Boehringer Ingelheim Investigational Site	Eugene	Oregon	United States
39	1245.33.01018 Boehringer Ingelheim Investigational Site	Altoona	Pennsylvania	United States
40	1245.33.01041 Boehringer Ingelheim Investigational Site	Carlisle	Pennsylvania	United States
41	1245.33.01042 Boehringer Ingelheim Investigational Site	Landsdale	Pennsylvania	United States
42	1245.33.01004 Boehringer Ingelheim Investigational Site	Greer	South Carolina	United States
43	1245.33.01036 Boehringer Ingelheim Investigational Site	Mt. Pleasant	South Carolina	United States
44	1245.33.01035 Boehringer Ingelheim Investigational Site	Seneca	South Carolina	United States
45	1245.33.01058 Boehringer Ingelheim Investigational Site	Kingsport	Tennessee	United States
46	1245.33.01037 Boehringer Ingelheim Investigational Site	Memphis	Tennessee	United States
47	1245.33.01023 Boehringer Ingelheim Investigational Site	Dallas	Texas	United States
48	1245.33.01030 Boehringer Ingelheim Investigational Site	Dallas	Texas	United States
49	1245.33.01006 Boehringer Ingelheim Investigational Site	Houston	Texas	United States
50	1245.33.01011 Boehringer Ingelheim Investigational Site	Houston	Texas	United States
51	1245.33.01002 Boehringer Ingelheim Investigational Site	Sugar Land	Texas	United States
52	1245.33.01049 Boehringer Ingelheim Investigational Site	Salt Lake City	Utah	United States
53	1245.33.01015 Boehringer Ingelheim Investigational Site	Norfolk	Virginia	United States
54	1245.33.01009 Boehringer Ingelheim Investigational Site	Richmond	Virginia	United States
55	1245.33.01010 Boehringer Ingelheim Investigational Site	Federal Way	Washington	United States
56	1245.33.01061 Boehringer Ingelheim Investigational Site	Milwaukee	Wisconsin	United States
57	1245.33.45006 Boehringer Ingelheim Investigational Site	Aalborg		Denmark
58	1245.33.45001 Boehringer Ingelheim Investigational Site	Aarhus C		Denmark
59	1245.33.45011 Boehringer Ingelheim Investigational Site	Aarhus C		Denmark
60	1245.33.45013 Boehringer Ingelheim Investigational Site	Aarhus C		Denmark
61	1245.33.45004 Boehringer Ingelheim Investigational Site	Gentofte		Denmark
62	1245.33.45008 Boehringer Ingelheim Investigational Site	Hillerød		Denmark
63	1245.33.45002 Boehringer Ingelheim Investigational Site	Hvidovre		Denmark
64	1245.33.45003 Boehringer Ingelheim Investigational Site	København NV		Denmark
65	1245.33.3301A Boehringer Ingelheim Investigational Site	Bondy Cedex		France
66	1245.33.3302A Boehringer Ingelheim Investigational Site	Corbeil Essonnes		France
67	1245.33.3305A Boehringer Ingelheim Investigational Site	La Rochelle Cedex 1		France
68	1245.33.3306A Boehringer Ingelheim Investigational Site	Marseille		France
69	1245.33.3308A Boehringer Ingelheim Investigational Site	Montbrison		France
70	1245.33.3309A Boehringer Ingelheim Investigational Site	Nanterre Cedex		France
71	1245.33.3310A Boehringer Ingelheim Investigational Site	Nantes		France
72	1245.33.3304A Boehringer Ingelheim Investigational Site	Narbonne Cedex		France
73	1245.33.3303A Boehringer Ingelheim Investigational Site	Saint Mandé		France
74	1245.33.35302 Boehringer Ingelheim Investigational Site	Dublin		Ireland
75	1245.33.35303 Boehringer Ingelheim Investigational Site	Dublin		Ireland
76	1245.33.35304 Boehringer Ingelheim Investigational Site	Dublin		Ireland
77	1245.33.82008 Boehringer Ingelheim Investigational Site	Daejeon		Korea, Republic of
78	1245.33.82007 Boehringer Ingelheim Investigational Site	Gwangju		Korea, Republic of
79	1245.33.82001 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
80	1245.33.82003 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
81	1245.33.82004 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
82	1245.33.82005 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
83	1245.33.82006 Boehringer Ingelheim Investigational Site	Wonju		Korea, Republic of
84	1245.33.82002 Boehringer Ingelheim Investigational Site	Yangsan		Korea, Republic of
85	1245.33.35104 Boehringer Ingelheim Investigational Site	Aveiro		Portugal
86	1245.33.35101 Boehringer Ingelheim Investigational Site	Coimbra		Portugal
87	1245.33.35102 Boehringer Ingelheim Investigational Site	Lisboa		Portugal
88	1245.33.35106 Boehringer Ingelheim Investigational Site	Lisboa		Portugal
89	1245.33.35107 Boehringer Ingelheim Investigational Site	Lisboa		Portugal
90	1245.33.44001 Boehringer Ingelheim Investigational Site	Bath		United Kingdom
91	1245.33.44003 Boehringer Ingelheim Investigational Site	Birmingham		United Kingdom
92	1245.33.44006 Boehringer Ingelheim Investigational Site	Blackburn		United Kingdom
93	1245.33.44005 Boehringer Ingelheim Investigational Site	Dorking		United Kingdom
94	1245.33.44009 Boehringer Ingelheim Investigational Site	Headington		United Kingdom
95	1245.33.44008 Boehringer Ingelheim Investigational Site	Leicester		United Kingdom
96	1245.33.44004 Boehringer Ingelheim Investigational Site	Liverpool		United Kingdom
97	1245.33.44007 Boehringer Ingelheim Investigational Site	Wembley		United Kingdom
98	1245.33.44002 Boehringer Ingelheim Investigational Site	Whitstable		United Kingdom
99	1245.33.44010 Boehringer Ingelheim Investigational Site	Wymondham		United Kingdom

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01011868
• Other Study ID Numbers: 1245.33; 2009-013668-38
• First Posted: Nov 11, 2009
• Last Update Posted: Sep 30, 2014
• Last Verified: Sep 1, 2014

• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Empagliflozin

Study Results

Participant Flow

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Period Title: After Week 18 Follow-up
STARTED	170	169	155
COMPLETED	147	153	129
NOT COMPLETED	23	16	26
Period Title: After Week 18 Follow-up
STARTED	170	169	155
COMPLETED	118	131	111
NOT COMPLETED	52	38	44

Baseline Characteristics

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg	Total
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily	Total of all reporting groups
Overall Participants	170	169	155	494
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.1 (9.4)	58.6 (9.8)	59.9 (10.5)	58.8 (9.9)
Sex: Female, Male (Count of Participants)
Female	80 47.1%	76 45%	62 40%	218 44.1%
Male	90 52.9%	93 55%	93 60%	276 55.9%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) After 18 Weeks of Treatment
Description	Change from baseline in Glycosylated haemoglobin A1c (HbA1c) after 18 weeks of treatment
Time Frame	Baseline and 18 weeks

Outcome Measure Data

Analysis Population Description

FAS18-completers-included FAS patients not prematurely discontinue prior to Week 18, completed required minimum treatment duration, and had an on treatment HbA1c value within Week 18 time window. Values after start of antidiabetic rescue therapy were set to missing and last observation carried forward (LOCF-18) was used for imputation. (LOCF-18)

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	125	132	117
Mean (Standard Error) [percentage of HbA1c]	0.03 (0.07)	-0.58 (0.07)	-0.75 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	The null and alternative hypotheses to be tested: H0,1: No difference in change from baseline to Week 18 in HbA1c between empagliflozin 10 mg and placebo H1,1: A difference in change from baseline to Week 18 in HbA1c between empagliflozin 10 mg and placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Hypotheses were tested at significance level of 0.025, which is half of overall alpha of 0.05, split equally between 2 treatment comparisons. This maintained the overall type-I (alpha) at 5%. There was no a priori assumption on testing order.
	Method	ANCOVA
	Comments	ANCOVA that included treatment group and geographic region as fixed effects along with baseline HbA1c as covariate.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 97.5%; -0.78 to -0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	The primary analysis consisted of the pair-wise comparisons between each dose of empagliflozin versus placebo using the adjusted means from the model.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	The null and alternative hypotheses to be tested: H0,2: No difference in change from baseline to Week 18 in HbA1c between empagliflozin 25 mg and placebo H1,2: A difference in change from baseline to Week 18 in HbA1c between empagliflozin 25 mg and placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Hypotheses were tested at significance level of 0.025, which is half of overall alpha of 0.05, split equally between 2 treatment comparisons. This maintained the overall type-I (alpha) at 5%. There was no a priori assumption on testing order.
	Method	ANCOVA
	Comments	ANCOVA that included treatment group and geographic region as fixed effects along with baseline HbA1c as covariate.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.70
	Confidence Interval	(2-Sided) 97.5%; -0.93 to -0.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments	The primary analysis consisted of the pair-wise comparisons between each dose of empagliflozin versus placebo using the adjusted means from the model.

2. Secondary Outcome

Title	Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5%) After 18, 54 and 78 Weeks of Treatment
Description	Patients that had a reduction in HbA1c of at least 0.5% from baseline to 18, 54 and 78 weeks of treatment
Time Frame	Baseline and 18, 54 and 78 weeks

Outcome Measure Data

Analysis Population Description

FAS with non-completers considered failure (NCF)

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	170	169	155
18 weeks	27 15.9%	85 50.3%	73 47.1%
54 weeks	30 17.6%	72 42.6%	69 44.5%
78 weeks	27 15.9%	59 34.9%	61 39.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Empagliflozin 10 mg vs Placebo at 18 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.518
	Confidence Interval	(2-Sided) 95%; 3.262 to 9.334
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Empagliflozin 25 mg vs Placebo at 18 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.883
	Confidence Interval	(2-Sided) 95%; 2.859 to 8.338
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Empagliflozin 10 mg vs Placebo at 54 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.471
	Confidence Interval	(2-Sided) 95%; 2.077 to 5.802
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Empagliflozin 25 mg vs Placebo at 54 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.825
	Confidence Interval	(2-Sided) 95%; 2.268 to 6.451
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Empagliflozin 10 mg vs Placebo at 78 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.802
	Confidence Interval	(2-Sided) 95%; 1.639 to 4.789
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Empagliflozin 25 mg vs Placebo at 78 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.527
	Confidence Interval	(2-Sided) 95%; 2.051 to 6.066
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) After 18, 54 and 78 Weeks of Treatment
Description	Change from baseline in fasting plasma glucose (FPG) after 18, 54 and 78 weeks of treatment
Time Frame	Baseline, 18, 54 and 78 weeks

Outcome Measure Data

Analysis Population Description

FAS observed cases (OC)

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	135	138	120
week 18 Change from BL	9.81 (5.48)	-14.79 (3.93)	-27.03 (3.92)
week 54 Change from BL (N=103,111,99)	0.91 (5.08)	-9.59 (4.69)	-23.75 (4.62)
week 78 Change from BL (N=92,104,92)	-5.53 (4.95)	-7.75 (4.66)	-21.62 (5.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 18 - Empagliflozin 10 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-28.40
	Confidence Interval	(2-Sided) 95%; -37.54 to -19.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.65
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 18 - Empagliflozin 25 mg vs Placebo at 18 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-34.21
	Confidence Interval	(2-Sided) 95%; -43.67 to -24.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.81
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 54 - Empagliflozin 10 mg vs Placebo at 18 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0328
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-10.75
	Confidence Interval	(2-Sided) 95%; -20.62 to -0.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.02
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 54 - Empagliflozin 25 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-19.16
	Confidence Interval	(2-Sided) 95%; -29.31 to -9.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.16
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 78 - Empagliflozin 10 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3216
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-5.03
	Confidence Interval	(2-Sided) 95%; -15.01 to 4.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.07
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 78 - Empagliflozin 25 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0229
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-11.95
	Confidence Interval	(2-Sided) 95%; -22.24 to -1.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.23
	Estimation Comments

4. Secondary Outcome

Title	Percent Change From Baseline in Fasting Plasma Glucose (FPG) After 18, 54 and 78 Weeks of Treatment
Description	Percent change from baseline in fasting plasma glucose (FPG) after 18, 54 and 78 weeks of treatment
Time Frame	Baseline, 18, 54 and 78 weeks

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	135	138	120
week 18 % CHG	19.02 (6.32)	-2.80 (3.17)	-13.43 (2.39)
week 54 % CHG (N=103,111,99)	9.67 (5.58)	0.67 (4.05)	-11.59 (3.04)
week 78 % CHG (N=92,104,92)	4.75 (5.67)	2.43 (4.18)	-9.52 (3.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 18 - Empagliflozin 10 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-25.12
	Confidence Interval	(2-Sided) 95%; -35.38 to -14.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.22
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 18 - Empagliflozin 25 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-31.01
	Confidence Interval	(2-Sided) 95%; -41.62 to -20.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 54 - Empagliflozin 10 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0484
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-10.20
	Confidence Interval	(2-Sided) 95%; -20.33 to -0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.15
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 54 - Empagliflozin 25 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-19.42
	Confidence Interval	(2-Sided) 95%; -29.84 to -8.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.30
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 78 - Empagliflozin 10 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3517
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-4.73
	Confidence Interval	() 95%; -14.71 to 5.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.07
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 78 - Empagliflozin 25 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0185
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline FPG, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-12.39
	Confidence Interval	(2-Sided) 95%; -22.69 to -2.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.23
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Basal Insulin Dose/Day After 54 and 78 Weeks of Treatment
Description	Change from baseline in basal insulin dose/day after 54 and 78 weeks of treatment
Time Frame	Baseline, 54 and 78 weeks

Outcome Measure Data

Analysis Population Description

FAS (OC-78) for week 54 FAS78-completers (LOCF-78) for week 78 - Values after start of antidiabetic rescue therapy except changes in basal insulin dose were set to missing and last observation carried forward (LOCF) was used for imputation of missing values

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	112	127	110
week 54 (N=112,122,104)	5.39 (1.60)	-1.20 (1.40)	-1.12 (1.27)
week 78	4.79 (2.06)	-0.70 (1.85)	-0.39 (1.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Empagliflozin versus Placebo 10 mg at 54 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0213
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-5.58
	Confidence Interval	(2-Sided) 95%; -10.32 to -0.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.40
	Estimation Comments	Week 54 model includes, baseline basal insulin, baseline HbA1c as linear covariate(s), geographical region, treatment, visit and visit by treatment interaction as fixed effects.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Empagliflozin versus Placebo 25 mg at 54 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0237
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-5.69
	Confidence Interval	(2-Sided) 95%; -10.62 to -0.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.49
	Estimation Comments	Week 54 model includes, baseline basal insulin, baseline HbA1c as linear covariate(s), geographical region, treatment, visit and visit by treatment interaction as fixed effect(s).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Empagliflozin versus Placebo 10 mg at 78 weeks H0,1a: No difference in change from baseline to Week 78 in basal insulin dose between Empagliflozin 10 mg and placebo H1,1a: A difference in change from baseline to Week 78 in basal insulin dose between Empagliflozin 10 mg and placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments	Hierarchical testing approach was applied to Empagliflozin 10 mg vs Placebo. If null hypothesis is rejected for the primary endpoint, at 0.025 (2-sided), testing of the key secondary endpoints continued in a hierarchical fashion for the same dose.
	Method	ANCOVA
	Comments	Model for Week 78 includes baseline basal insulin, baseline HbA1c as linear covariate(s) and geographical region, treatment as fixed effect(s)
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-6.66
	Confidence Interval	(2-Sided) 97.5%; -11.56 to -1.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.18
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Empagliflozin versus Placebo 25 mg at 78 weeks H0,1a: No difference in change from baseline to Week 78 in basal insulin dose between Empagliflozin 25 mg and placebo H1,1a: A difference in change from baseline to Week 78 in basal insulin dose between Empagliflozin 25 mg and placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0090
	Comments	Hierarchical testing approach was applied to Empagliflozin 25 mg vs Placebo. If null hypothesis is rejected for the primary endpoint, at 0.025 (2-sided), testing of the key secondary endpoints continued in a hierarchical fashion for the same dose.
	Method	ANCOVA
	Comments	Model for Week 78 includes baseline basal insulin, baseline HbA1c as linear covariate(s) and geographical region, treatment as fixed effect(s)
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-5.92
	Confidence Interval	(2-Sided) 97.5%; -11.00 to -0.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.25
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Body Weight After 18, 54 and 78 Weeks of Treatment
Description	Change from baseline in body weight after 18, 54 and 78 weeks of treatment
Time Frame	Baseline, 18, 54, 78 weeks

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	141	148	125
18 weeks	-0.04 (0.21)	-2.06 (0.22)	-0.91 (1.27)
54 weeks (N=114,120,106)	-0.52 (0.32)	-2.28 (0.33)	-2.23 (0.35)
78 weeks (N=100,113,96)	1.12 (1.28)	-2.61 (0.31)	-1.99 (0.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 18 - Empagliflozin 10 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0320
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-2.04
	Confidence Interval	(2-Sided) 95%; -3.90 to -0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.95
	Estimation Comments	Model includes baseline weight, baseline HbA1c as linear covariates, geographical region, treatment, visit and visit by treatment interaction as fixed effects

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 18 - Empagliflozin 25 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3818
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) 95%; -2.81 to 1.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.99
	Estimation Comments	Model includes baseline weight, baseline HbA1c as linear covariates, geographical region, treatment, visit and visit by treatment interaction as fixed effects

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 54 - Empagliflozin 10 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.97
	Confidence Interval	(2-Sided) 95%; -2.89 to -1.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.47
	Estimation Comments	Model includes baseline weight, baseline HbA1c as linear covariates, geographical region, treatment, visit and visit by treatment interaction as fixed effects

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 54 - Empagliflozin 25 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-2.17
	Confidence Interval	(2-Sided) 95%; -3.13 to -1.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.49
	Estimation Comments	Model includes baseline weight, baseline HbA1c as linear covariates, geographical region, treatment, visit and visit by treatment interaction as fixed effects

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 78 - Empagliflozin 10 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-3.63
	Confidence Interval	(2-Sided) 95%; -5.81 to -1.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.10
	Estimation Comments	Model includes baseline weight, baseline HbA1c as linear covariates, geographical region, treatment, visit and visit by treatment interaction as fixed effects

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 78 - Empagliflozin 25 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0073
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes, baseline weight, baseline HbA1c as covariates, geographic region, treatment, visit and visit by treatment interaction as fixed effects
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-3.12
	Confidence Interval	(2-Sided) 95%; -5.39 to -0.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.15
	Estimation Comments	Model includes baseline weight, baseline HbA1c as linear covariates, geographical region, treatment, visit and visit by treatment interaction as fixed effects

7. Secondary Outcome

Title	Change From Baseline in Body Weight at Follow-up
Description	Change from baseline in body weight at follow up (82 weeks)
Time Frame	Baseline and 82 weeks

Outcome Measure Data

Analysis Population Description

FAS-FU (OR)

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	111	119	112
Follow-up	90.56 (25.87)	90.44 (19.35)	93.98 (20.87)
Follow-up change from baseline	0.92 (12.20)	-2.02 (4.04)	-1.05 (3.96)
Change from last value on treatment N=111,118,109	-0.23 (16.84)	0.62 (2.11)	1.34 (1.90)

8. Secondary Outcome

Title	Change From Baseline in HbA1c After 54 and 78 Weeks of Treatment
Description	Change from baseline in HbA1c after 54 and 78 weeks of treatment
Time Frame	Baseline, 54 and 78 weeks

Outcome Measure Data

Analysis Population Description

Week 54 - FAS (OC-78) Week 78 - FAS78-completers (LOCF-78)

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	113	127	110
Week 54 (N=113,121,107)	-0.06 (0.08)	-0.59 (0.08)	-0.84 (0.09)
Week 78 (N=112,127,110)	-0.05 (0.10)	-0.51 (0.09)	-0.68 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 54 - Empagliflozin 10 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95%; -0.68 to -0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments	Model includes baseline HbA1c as linear covariate(s), geographical region, treatment, visit and visit by treatment interaction as fixed effect(s).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 54 - Empagliflozin 25 mg vs Placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.74
	Confidence Interval	(2-Sided) 95%; -0.95 to -0.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments	Model includes baseline HbA1c as linear covariate(s), geographical region, treatment, visit and visit by treatment interaction as fixed effect(s).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Change from BL at week 78 - Empagliflozin 10 mg vs Placebo H0,1b: The change from baseline to Week 78 in HbA1c between empagliflozin 10 mg and placebo ≥0.3% H1,1b: The change from baseline to Week 78 in HbA1c between empagliflozin 10 mg and placebo <0.3%
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	For non-inferiority, a one-sided test at the significance level of 0.0125 was performed using a chosen margin of 0.3% difference between each dose of empagliflozin and placebo. If the non-inferiority of empagliflozin to placebo with respect to change from baseline in HbA1c after 78 weeks of treatment could be concluded for a specific dose, subsequent testing of superiority was performed at the significance level of 0.025 for the relevant empagliflozin dose versus placebo comparison.
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Hierarchical testing approach was applied to Empagliflozin 10 mg vs Placebo. If null hypothesis is rejected for the primary endpoint, at 0.025 (2-sided), testing of the key secondary endpoints continued in a hierarchical fashion for the same dose.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 97.5%; -0.73 to -0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments	Model includes baseline HbA1c as linear covariate(s), geographical region, treatment as fixed effect(s).

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Change from BL at week 78 - Empagliflozin 25 mg vs Placebo H0,1b: The change from baseline to Week 78 in HbA1c between empagliflozin 25 mg and placebo ≥0.3% H1,1b: The change from baseline to Week 78 in HbA1c between empagliflozin 25 mg and placebo <0.3%
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	For non-inferiority, a one-sided test at the significance level of 0.0125 was performed using a chosen margin of 0.3% difference between each dose of empagliflozin and placebo. If the non-inferiority of empagliflozin to placebo with respect to change from baseline in HbA1c after 78 weeks of treatment could be concluded for a specific dose, subsequent testing of superiority was performed at the significance level of 0.025 for the relevant empagliflozin dose versus placebo comparison.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Hierarchical testing approach was applied to Empagliflozin 25 mg vs Placebo. If null hypothesis is rejected for the primary endpoint, at 0.025 (2-sided), testing of the key secondary endpoints continued in a hierarchical fashion for the same dose.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 97.5%; -0.90 to -0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments	Model includes baseline HbA1c as linear covariate(s), geographical region, treatment as fixed effect(s).

9. Other Pre-specified Outcome

Title	Confirmed Hypoglycemic Events
Description	Confirmed hypoglycemic events refer to all hypoglycemic events that had a glucose value ≤70 ml/dL or where assistance was required. Symptomatic hypoglycemic events were to be reported as adverse events. Investigator-defined hypoglycaemia adverse events include all events that investigator marked as 'Hypoglycaemic event' in CRFs, regardless of the reported term or blood glucose value. It may include hypoglycemia itself as reported term or any other symptoms that that investigator may have attributed to hypoglycemia (e.g. dizziness, hyperhidrosis, and asthenia).
Time Frame	During the course of the study (82 weeks)

Outcome Measure Data

Analysis Population Description

Treated set (TS). Treatment assignment as first medication taken.

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	170	169	155
Number [participants]	60 35.3%	61 36.1%	56 36.1%

10. Secondary Outcome

Title	The Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <7.0% After 18, 54, and 78 Weeks of Treatment
Description	The occurrence of treat to target efficacy response, that is an HbA1c under treatment of <7.0% After 18, 54, and 78 weeks of treatment
Time Frame	Baseline, 18, 54 and 78 weeks

Outcome Measure Data

Analysis Population Description

FAS (NCF)

Arm/Group Title	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral Placebo	Empagliflozin 10 mg orally once daily	Empagliflozin 25 mg orally once daily
Measure Participants	165	167	154
18 weeks	9 5.3%	30 17.8%	30 19.4%
54 weeks	14 8.2%	23 13.6%	27 17.4%
78 weeks	11 6.5%	20 11.8%	27 17.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Empagliflozin 10 mg vs Placebo at 18 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.096
	Confidence Interval	(2-Sided) 95%; 1.846 to 9.088
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Empagliflozin 25 mg vs Placebo at 18 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.636
	Confidence Interval	(2-Sided) 95%; 2.083 to 10.321
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Empagliflozin 10 mg vs Placebo at 54 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1248
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.750
	Confidence Interval	(2-Sided) 95%; 0.856 to 3.575
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Empagliflozin 25 mg vs Placebo at 54 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0132
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.423
	Confidence Interval	(2-Sided) 95%; 1.203 to 4.879
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Empagliflozin 10 mg vs Placebo at 78 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0986
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.939
	Confidence Interval	(2-Sided) 95%; 0.884 to 4.256
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	Empagliflozin 25 mg vs Placebo at 78 weeks
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression includes treatment, geographical region and baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.239
	Confidence Interval	(2-Sided) 95%; 1.518 to 6.911
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	During the course of the study (82 weeks)
Arm/Group Title	Placebo		Empagliflozin 10 mg		Empagliflozin 25 mg
Arm/Group Description	Oral Placebo		Empagliflozin 10 mg orally once daily		Empagliflozin 25 mg orally once daily
All Cause Mortality
	Placebo		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/170 (16.5%)		28/169 (16.6%)		28/155 (18.1%)
Cardiac disorders
Bradycardia	0/170 (0%)		2/169 (1.2%)		0/155 (0%)
Coronary artery disease	2/170 (1.2%)		2/169 (1.2%)		0/155 (0%)
Acute myocardial infarction	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Angina pectoris	1/170 (0.6%)		1/169 (0.6%)		0/155 (0%)
Angina unstable	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Atrial fibrillation	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Atrial flutter	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Cardiac arrest	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Coronary artery occlusion	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Myocardial infarction	0/170 (0%)		1/169 (0.6%)		1/155 (0.6%)
Myocardial ischaemia	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Right ventricular failure	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Congenital, familial and genetic disorders
Arnold-Chiari malformation	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Ear and labyrinth disorders
Vertigo	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Eye disorders
Macular fibrosis	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Retinal detachment	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Vitreous haemorrhage	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Gastrointestinal disorders
Abdominal distension	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Constipation	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Enterocutaneous fistula	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Gastric ulcer haemorrhage	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Haematochezia	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Oesophageal ulcer	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Oesophagitis	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Pancreatitis acute	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Rectal haemorrhage	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
General disorders
Chest discomfort	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Chest pain	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Device failure	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Non-cardiac chest pain	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Infections and infestations
Cystitis	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Diverticulitis	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Enterocolitis infectious	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Osteomyelitis	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Pneumonia	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Pyelonephritis	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Scrotal abscess	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Sepsis	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Sinusitis	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Urinary tract infection	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Injury, poisoning and procedural complications
Road traffic accident	0/170 (0%)		2/169 (1.2%)		0/155 (0%)
Accident at home	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Accident at work	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Concussion	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Contusion	0/170 (0%)		1/169 (0.6%)		1/155 (0.6%)
Fall	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Ligament sprain	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Limb crushing injury	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Overdose	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Radius fracture	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Skeletal injury	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Wrist fracture	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Investigations
Hepatic enzyme increased	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Metabolism and nutrition disorders
Dehydration	1/170 (0.6%)		1/169 (0.6%)		0/155 (0%)
Hypoglycaemia	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Hypovolaemia	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/170 (0%)		2/169 (1.2%)		1/155 (0.6%)
Arthralgia	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Costochondritis	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Joint contracture	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Joint instability	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Musculoskeletal stiffness	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Rotator cuff syndrome	1/170 (0.6%)		1/169 (0.6%)		0/155 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Thyroid cancer	0/170 (0%)		0/169 (0%)		2/155 (1.3%)
Prostate cancer	2/170 (1.2%)		0/169 (0%)		0/155 (0%)
Bladder cancer	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Breast cancer	1/170 (0.6%)		1/169 (0.6%)		0/155 (0%)
Colon cancer	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Gastric cancer	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Lung neoplasm malignant	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Malignant fibrous histiocytoma	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Mycosis fungoides	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Pancreatic carcinoma	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Prostatic adenoma	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Squamous cell carcinoma of the cervix	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Nervous system disorders
Syncope	0/170 (0%)		2/169 (1.2%)		0/155 (0%)
Carotid artery occlusion	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Carotid artery stenosis	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Cerebral haemorrhage	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Cerebral infarction	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Cerebrovascular accident	0/170 (0%)		1/169 (0.6%)		1/155 (0.6%)
Convulsion	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Haemorrhagic stroke	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Sciatica	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Transient ischaemic attack	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Psychiatric disorders
Depression	1/170 (0.6%)		1/169 (0.6%)		0/155 (0%)
Renal and urinary disorders
Nephrolithiasis	2/170 (1.2%)		0/169 (0%)		0/155 (0%)
Nephrotic syndrome	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Neurogenic bladder	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Renal failure	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Renal failure acute	0/170 (0%)		1/169 (0.6%)		1/155 (0.6%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Dyspnoea	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Vocal cord polyp	0/170 (0%)		1/169 (0.6%)		0/155 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Surgical and medical procedures
Carotid endarterectomy	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Vascular disorders
Femoral arterial stenosis	0/170 (0%)		0/169 (0%)		1/155 (0.6%)
Orthostatic hypotension	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Peripheral vascular disorder	1/170 (0.6%)		0/169 (0%)		0/155 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	115/170 (67.6%)		110/169 (65.1%)		95/155 (61.3%)
Gastrointestinal disorders
Diarrhoea	13/170 (7.6%)		10/169 (5.9%)		11/155 (7.1%)
Nausea	12/170 (7.1%)		9/169 (5.3%)		8/155 (5.2%)
Vomiting	5/170 (2.9%)		4/169 (2.4%)		8/155 (5.2%)
General disorders
Fatigue	2/170 (1.2%)		10/169 (5.9%)		4/155 (2.6%)
Infections and infestations
Nasopharyngitis	22/170 (12.9%)		20/169 (11.8%)		17/155 (11%)
Urinary tract infection	13/170 (7.6%)		21/169 (12.4%)		16/155 (10.3%)
Upper respiratory tract infection	10/170 (5.9%)		18/169 (10.7%)		13/155 (8.4%)
Metabolism and nutrition disorders
Hypoglycaemia	56/170 (32.9%)		56/169 (33.1%)		55/155 (35.5%)
Hyperglycaemia	17/170 (10%)		16/169 (9.5%)		15/155 (9.7%)
Musculoskeletal and connective tissue disorders
Back pain	13/170 (7.6%)		11/169 (6.5%)		13/155 (8.4%)
Arthralgia	9/170 (5.3%)		6/169 (3.6%)		8/155 (5.2%)
Nervous system disorders
Dizziness	12/170 (7.1%)		18/169 (10.7%)		7/155 (4.5%)
Headache	5/170 (2.9%)		5/169 (3%)		8/155 (5.2%)
Psychiatric disorders
Depression	3/170 (1.8%)		10/169 (5.9%)		2/155 (1.3%)
Respiratory, thoracic and mediastinal disorders
Cough	9/170 (5.3%)		6/169 (3.6%)		4/155 (2.6%)
Vascular disorders
Hypertension	12/170 (7.1%)		1/169 (0.6%)		3/155 (1.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.