Trial Outcomes & Findings for Empagliflozin as Adjunctive to Insulin Therapy Over 26 Weeks in Patients With T1DM (EASE-3) (NCT NCT02580591)

Last Updated: 2018-11-02

Results Overview

Change from baseline in Glycated hemoglobin (HbA1c) for full analysis set (FAS) (observed cases \[OC\]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

977 participants

Primary outcome timeframe

Baseline to week 26

Results posted on

2018-11-02

Participant Flow

A randomized, placebo-controlled, double-blind, parallel-group study compared 3 doses of empagliflozin (2.5 milligram (mg), 10 mg, and 25 mg) with placebo in patients with type 1 diabetes mellitus (T1DM) as adjunctive to optimized insulin therapy.

6-Week T1DM therapy (insulin) optimisation period followed by a 2-Week placebo run-in period before randomization. Patients who successfully completed both of the periods were randomized into the 26-Week double-blind treatment period. All treatments were administered in addition to optimized insulin therapy.

Participant milestones

Participant milestones
Measure	Placebo Matching Empagliflozin Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Overall Study STARTED	242	242	248	245
Overall Study Treated	241	241	248	245
Overall Study COMPLETED	224	232	235	233
Overall Study NOT COMPLETED	18	10	13	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Matching Empagliflozin Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Overall Study Adverse Event	0	1	2	5
Overall Study Protocol Violation	3	2	1	1
Overall Study Lost to Follow-up	5	3	3	1
Overall Study Withdrawal by Subject	6	1	2	3
Overall Study Not treated	1	1	0	0
Overall Study Other than specified	3	2	5	2

Baseline Characteristics

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Matching Empagliflozin n=242 Participants Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) n=242 Participants Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg n=248 Participants Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg n=245 Participants Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Total n=977 Participants Total of all reporting groups
Age, Continuous	42.3 Years STANDARD_DEVIATION 13.2 • n=5 Participants • RS	43.4 Years STANDARD_DEVIATION 14.3 • n=7 Participants • RS	42.3 Years STANDARD_DEVIATION 13.2 • n=5 Participants • RS	44.4 Years STANDARD_DEVIATION 13.6 • n=4 Participants • RS	43.1 Years STANDARD_DEVIATION 13.6 • n=21 Participants • RS
Sex: Female, Male Female	126 Participants n=5 Participants • RS	120 Participants n=7 Participants • RS	132 Participants n=5 Participants • RS	121 Participants n=4 Participants • RS	499 Participants n=21 Participants • RS
Sex: Female, Male Male	116 Participants n=5 Participants • RS	122 Participants n=7 Participants • RS	116 Participants n=5 Participants • RS	124 Participants n=4 Participants • RS	478 Participants n=21 Participants • RS
Ethnicity (NIH/OMB) Hispanic or Latino	215 Participants n=5 Participants • RS	220 Participants n=7 Participants • RS	233 Participants n=5 Participants • RS	224 Participants n=4 Participants • RS	892 Participants n=21 Participants • RS
Ethnicity (NIH/OMB) Not Hispanic or Latino	27 Participants n=5 Participants • RS	22 Participants n=7 Participants • RS	15 Participants n=5 Participants • RS	21 Participants n=4 Participants • RS	85 Participants n=21 Participants • RS
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants • RS	0 Participants n=7 Participants • RS	0 Participants n=5 Participants • RS	0 Participants n=4 Participants • RS	0 Participants n=21 Participants • RS
Race (NIH/OMB) American Indian or Alaska Native	7 Participants n=5 Participants • RS	0 Participants n=7 Participants • RS	1 Participants n=5 Participants • RS	5 Participants n=4 Participants • RS	13 Participants n=21 Participants • RS
Race (NIH/OMB) Asian	2 Participants n=5 Participants • RS	2 Participants n=7 Participants • RS	2 Participants n=5 Participants • RS	5 Participants n=4 Participants • RS	11 Participants n=21 Participants • RS
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants • RS	0 Participants n=7 Participants • RS	0 Participants n=5 Participants • RS	0 Participants n=4 Participants • RS	1 Participants n=21 Participants • RS
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants • RS	3 Participants n=7 Participants • RS	10 Participants n=5 Participants • RS	4 Participants n=4 Participants • RS	22 Participants n=21 Participants • RS
Race (NIH/OMB) White	227 Participants n=5 Participants • RS	234 Participants n=7 Participants • RS	234 Participants n=5 Participants • RS	231 Participants n=4 Participants • RS	926 Participants n=21 Participants • RS
Race (NIH/OMB) More than one race	0 Participants n=5 Participants • RS	3 Participants n=7 Participants • RS	1 Participants n=5 Participants • RS	0 Participants n=4 Participants • RS	4 Participants n=21 Participants • RS
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants • RS	0 Participants n=7 Participants • RS	0 Participants n=5 Participants • RS	0 Participants n=4 Participants • RS	0 Participants n=21 Participants • RS

PRIMARY outcome

Timeframe: Baseline to week 26

Population: Full analysis set (FAS) (observed cases \[OC\]): Patients in the Treated Set (TS) who had a baseline and at least 1 on-treatment HbA1c measurement.

Outcome measures

Outcome measures
Measure	Placebo Matching Empagliflozin n=238 Participants Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) n=237 Participants Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg n=244 Participants Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg n=242 Participants Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Full Analysis Set (FAS) (Observed Cases [OC])	0.20 Percentage (%) Standard Error 0.05	-0.09 Percentage (%) Standard Error 0.05	-0.25 Percentage (%) Standard Error 0.05	-0.33 Percentage (%) Standard Error 0.05

PRIMARY outcome

Timeframe: Baseline to week 26

Population: Modified intention-to-treat set (mITT) (observed case - all data \[OC-AD\]): Patients in the TS who had a baseline and at least 1 post-baseline HbA1c measurement.

Change from baseline in Glycated hemoglobin (HbA1c) for modified intention-to-treat population set (mITT) (observed case - all data \[OC-AD\]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.

Outcome measures

Outcome measures
Measure	Placebo Matching Empagliflozin n=239 Participants Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) n=239 Participants Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg n=246 Participants Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg n=245 Participants Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD))	0.21 Percentage (%) Standard Error 0.05	-0.06 Percentage (%) Standard Error 0.05	-0.23 Percentage (%) Standard Error 0.05	-0.30 Percentage (%) Standard Error 0.05

SECONDARY outcome

Timeframe: Week 5 to Week 26, Week 1 to Week 26

Population: FAS (OC)

Rate per patient-year of investigator-reported symptomatic hypoglycemic adverse events (AEs) with confirmed plasma glucose (PG) \<54 milligram per deciliter (mg/dL) (\<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycemic AEs (i.e. all investigator-reported AEs that had confirmed PG \<54 mg/dL \[\<3.0 mmol/L\] with symptoms reported and all severe hypoglycemic events that were confirmed by adjudication) is presented for (i) From week 5 to 26 and (ii) From week 1 to 26. Least squares mean is actually an adjusted event rate. This is key secondary endpoints.

Outcome measures

Outcome measures
Measure	Placebo Matching Empagliflozin n=235 Participants Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) n=237 Participants Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg n=241 Participants Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg n=237 Participants Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) Week 5 to 26	6.13 Events per patient year Interval 4.83 to 7.78	5.77 Events per patient year Interval 4.53 to 7.34	7.37 Events per patient year Interval 5.83 to 9.31	6.25 Events per patient year Interval 4.94 to 7.91
Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) Week 1 to 26	6.62 Events per patient year Interval 5.3 to 8.27	6.17 Events per patient year Interval 4.93 to 7.73	8.33 Events per patient year Interval 6.7 to 10.37	6.96 Events per patient year Interval 5.58 to 8.67

SECONDARY outcome

Timeframe: Baseline to week 26

Population: FAS (OC)

Change from baseline in body weight is presented With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.

Outcome measures

Outcome measures
Measure	Placebo Matching Empagliflozin n=238 Participants Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) n=237 Participants Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg n=243 Participants Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg n=240 Participants Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Change From Baseline in Body Weight at Week 26	0.21 Kilogram (kg) Standard Error 0.20	-1.55 Kilogram (kg) Standard Error 0.20	-2.83 Kilogram (kg) Standard Error 0.20	-3.22 Kilogram (kg) Standard Error 0.20

SECONDARY outcome

Timeframe: Baseline to week 26

Population: FAS (OC)

Change from baseline in Total daily insulin dose (TDID) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.

Outcome measures

Outcome measures
Measure	Placebo Matching Empagliflozin n=217 Participants Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) n=223 Participants Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg n=217 Participants Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg n=220 Participants Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26	-0.011 Unit/kilogram (U/kg) Standard Error 0.007	-0.060 Unit/kilogram (U/kg) Standard Error 0.007	-0.080 Unit/kilogram (U/kg) Standard Error 0.007	-0.102 Unit/kilogram (U/kg) Standard Error 0.007

SECONDARY outcome

Timeframe: Baseline to week 26

Population: FAS observed cases excluding data after change in use of anti-hypertensives (OC-H)

Change from baseline in Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.

Outcome measures

Outcome measures
Measure	Placebo Matching Empagliflozin n=237 Participants Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) n=236 Participants Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg n=240 Participants Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg n=238 Participants Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 SBP	0.4 Millimeters of mercury (mmHg) Standard Error 0.7	-1.7 Millimeters of mercury (mmHg) Standard Error 0.7	-3.5 Millimeters of mercury (mmHg) Standard Error 0.7	-3.4 Millimeters of mercury (mmHg) Standard Error 0.7
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 DBP	0.0 Millimeters of mercury (mmHg) Standard Error 0.4	-0.4 Millimeters of mercury (mmHg) Standard Error 0.4	-1.8 Millimeters of mercury (mmHg) Standard Error 0.4	-1.5 Millimeters of mercury (mmHg) Standard Error 0.4

Adverse Events

Placebo Matching Empagliflozin

Serious events: 16 serious events

Other events: 153 other events

Deaths: 0 deaths

Empagliflozin 2.5 Milligram (mg)

Serious events: 13 serious events

Other events: 146 other events

Deaths: 0 deaths

Empagliflozin 10 mg

Serious events: 21 serious events

Other events: 172 other events

Deaths: 0 deaths

Empagliflozin 25 mg

Serious events: 16 serious events

Other events: 162 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo Matching Empagliflozin n=241 participants at risk Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 2.5 Milligram (mg) n=241 participants at risk Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 10 mg n=248 participants at risk Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Empagliflozin 25 mg n=245 participants at risk Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Infections and infestations Nasopharyngitis	10.0% 24/241 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	9.5% 23/241 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	8.9% 22/248 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	10.6% 26/245 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.
Infections and infestations Urinary tract infection	5.0% 12/241 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	5.0% 12/241 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	3.6% 9/248 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	6.5% 16/245 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.
Investigations Blood ketone body increased	1.2% 3/241 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	1.7% 4/241 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	6.0% 15/248 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	4.1% 10/245 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.
Metabolism and nutrition disorders Hypoglycaemia	59.8% 144/241 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	56.8% 137/241 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	65.3% 162/248 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.	61.6% 151/245 • From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days. Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

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Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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