BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME).

Study Description

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Brief Summary:

The aim of the present study is to investigate the safety of BI 10773 treatment in patients with Type 2 Diabetes Mellitus and high cardiovascular risk.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2	Drug: BI 10773 low dose; Drug: Placebo BI 10773 high dose; Drug: BI 10773 high dose; Drug: Placebo BI 10773 low dose	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	7064 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double
Primary Purpose:	Treatment
Official Title:	A Phase III, Multicentre, International, Randomised, Parallel Group, Double Blind Cardiovascular Safety Study of BI 10773 (10 mg and 25 mg Administered Orally Once Daily) Compared to Usual Care in Type 2 Diabetes Mellitus Patients With Increased Cardiovascular Risk
Study Start Date :	July 2010
Actual Primary Completion Date :	April 2015
Actual Study Completion Date :	April 2015

Arms and Interventions

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Arm	Intervention/treatment
Experimental: BI 10773 low dose; BI 10773 tablets once daily	Drug: BI 10773 low dose; BI 10773 tablets once daily Drug: Placebo BI 10773 high dose; Placebo tablets identical to BI 10773
Experimental: BI 10773 high dose; BI 10773 tablets once daily	Drug: BI 10773 high dose; BI 10773 tablets once daily Drug: Placebo BI 10773 low dose; Placebo tablets identical to BI 10773
Placebo Comparator: Placebo; Placebo tablets matching BI 10773	Drug: Placebo BI 10773 high dose; Placebo tablets identical to BI 10773 Drug: Placebo BI 10773 low dose; Placebo tablets identical to BI 10773

Outcome Measures

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Primary Outcome Measures :

1. Time to the First Occurrence of Any of the Following Adjudicated Components of the Primary Composite Endpoint (3-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), and Non-fatal Stroke. [ Time Frame: From randomisation to individual end of observation, up to 4.6 years ]

   Time to the first occurrence of any of the following adjudicated components of the primary composite endpoint (3-point major adverse cardiovascular events (MACE)): cardiovascular (CV) death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), and non-fatal stroke.

   Percentage of patients with the event are presented.

Secondary Outcome Measures :

1. Percentage of Participants With the Composite of All Events Adjudicated (4-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), Non-fatal Stroke and Hospitalization for Unstable Angina Pectoris [ Time Frame: From randomisation to individual end of observation, up to 4.6 years ]

   The composite of all events adjudicated (4-point MACE): cardiovascular death (including fatal stroke and fatal myocardial infarction), non-fatal myocardial infarction (excluding silent MI), non-fatal stroke and hospitalization for unstable angina pectoris.This is a key secondary endpoint of the trial.

   Percentage of patients with the event are presented.

2. Percentage of Participants With Silent MI [ Time Frame: From randomisation to individual end of observation, up to 4.6 years ]

   Silent MI; defined as presence in the ECG of:

   • Any Q-wave in leads V2-V3 ≥0.02 seconds or QS complex in leads V2 and V3
   • Q-wave ≥0.03 seconds and ≥0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V6; II, III, and aVF)
   • R-wave ≥0.04 seconds in V1-V2 and R/S ≥1 with a concordant positive T-wave in the absence of a conduction defect.

   It was also required that there had been no adjudicated and confirmed event of either acute MI, hospitalisation for unstable angina, coronary revascularisation procedures or stent thrombosis following randomisation up to and including the date of the specified ECG measurement.

   Percentage of patients with the event are presented.

3. Percentage of Participants With Heart Failure Requiring Hospitalisation (Adjudicated) [ Time Frame: From randomisation to individual end of observation, up to 4.6 years ]
   Heart failure requiring hospitalisation (adjudicated). Percentage of patients with the event are presented.
4. Percentage of Participants With New Onset Albuminuria [ Time Frame: From randomisation to individual end of observation, up to 4.6 years ]

   New onset albuminuria defined as urine albumin / creatinine ratio (UACR) ≥30 mg/g.

   Percentage of patients with the event are presented.

5. Percentage of Participants With New Onset Macroalbuminuria [ Time Frame: From randomisation to individual end of observation, up to 4.6 years ]
   New onset macroalbuminuria defined as UACR >300 mg/g. Percentage of patients with the event are presented.
6. Percentage of Participants With the Composite Microvascular Outcome [ Time Frame: From randomisation to individual end of observation, up to 4.6 years ]

   Composite microvascular outcome defined as:

   • Initiation of retinal photocoagulation
   • Vitreous haemorrhage
   • Diabetes-related blindness, or

   • New or worsening nephropathy defined as:

     • New onset of macroalbuminuria; or
     • Doubling of serum creatinine level accompanied by an eGFR (based on modification of diet in renal disease (MDRD) formula) ≤45 mL/min/1.73m2; or
     • Initiation of continuous renal replacement therapy, or
     • Death due to renal disease. Percentage of patients with the event are presented.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

1. Diagnosis of type 2 diabetes mellitus prior to informed consent
2. Male or female patients on diet and exercise regimen who are drug naive or pre treated with any background therapy. Antidiabetic therapy has to be unchanged for 12 weeks prior to randomization.
3. Glycosylated haemoglobin (HbA1c) of >= 7.0% and <=10% for patients on background therapy or HbA1c >= 7.0% and <= 9.0% for drug naive patients
4. Age >= 18 years
5. Body Mass index <= 45 at Visit 1
6. Signed and dated informed consent
7. High cardiovascular risk

Exclusion criteria:

1. Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
2. Indication of liver disease, defined by serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase ALT or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at screening and/or run in.
3. Planned cardiac surgery or angioplasty within 3 months
4. Impaired renal function, defined as Glomerular Filtration Rate <30 ml/min (severe renal impairment, Modification of Diet in Renal Disease formula) during screening or run in.
5. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
6. Blood dyscrasias or any disorders causing haemolysis or unstable Red Blood Cell (e.g. malaria, babesiosis, haemolytic anemia)
7. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
8. Contraindications to background therapy according to the local label
9. Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight
10. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except type 2 diabetes mellitus

11. Pre-menopausal women (last menstruation <+ 1 year prior to informed consent) who:

    • are nursing or pregnant or
    • are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems, oral, implantable or injectable contraceptives, sexual abstinence, double barrier method and vasectomised partner
12. Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake
13. Participation in another trial with an investigational drug within 30 days prior to informed consent
14. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial
15. Acute coronary syndrome, stroke or TIA within 2 months prior to informed consent

Contacts and Locations

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Sponsors and Collaborators

Boehringer Ingelheim

Eli Lilly and Company

Investigators

Study Chair:	Boehringer Ingelheim	Boehringer Ingelheim

More Information

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Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, Woerle HJ, Broedl UC, von Eynatten M, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease. Circulation. 2018 Jan 9;137(2):119-129. doi: 10.1161/CIRCULATIONAHA.117.028268. Epub 2017 Sep 13.

Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, Wanner C. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Aug;5(8):610-621. doi: 10.1016/S2213-8587(17)30182-1. Epub 2017 Jun 27.

Zinman B, Inzucchi SE, Lachin JM, Wanner C, Fitchett D, Kohler S, Mattheus M, Woerle HJ, Broedl UC, Johansen OE, Albers GW, Diener HC; EMPA-REG OUTCOME Investigators (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk. Stroke. 2017 May;48(5):1218-1225. doi: 10.1161/STROKEAHA.116.015756. Epub 2017 Apr 6.

Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34. doi: 10.1056/NEJMoa1515920. Epub 2016 Jun 14.

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.

Zinman B, Inzucchi SE, Lachin JM, Wanner C, Ferrari R, Fitchett D, Bluhmki E, Hantel S, Kempthorne-Rawson J, Newman J, Johansen OE, Woerle HJ, Broedl UC. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Diabetol. 2014 Jun 19;13:102. doi: 10.1186/1475-2840-13-102.

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01131676 History of Changes
Other Study ID Numbers:	1245.25; 2009-016178-33 ( EudraCT Number: EudraCT )
First Posted:	May 27, 2010
Results First Posted:	May 16, 2016
Last Update Posted:	May 16, 2016
Last Verified:	April 2016

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases	Endocrine System Diseases; Empagliflozin; Hypoglycemic Agents; Physiological Effects of Drugs