Clinical trial NCT01159600: Efficacy and Safety Study With Empagliflozin (BI 10773) vs. Placebo as add-on to Metformin or Metformin Plus Sulfonylurea Over 24 Weeks in Patients With Type 2 Diabetes
Official title: A Phase III Randomised, Double-blind, Placebo-controlled, Parallel Group, Efficacy and Safety Study of BI 10773 (10 mg, 25 mg) Administered Orally, Once Daily Over 24 Weeks in Patients With Type 2 Diabetes Mellitus With Insufficient Glycaemic Control Despite Treatment With Metformin Alone or Metformin in Combination With a Sulfonylurea
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Eli Lilly and Company
First posted: 2010-07-09
Enrollment: 1504
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of the current study is to investigate the efficacy, safety and tolerability of two doses of BI 10773 compared to placebo given for 24 weeks as add-on therapy to metformin or metformin plus sulfonylurea in patients with Typ 2 Diabetes Mellitus with insufficient glycaemic control.


Eligibility criteria: Inclusion criteria:

1. Diagnosis of type 2 diabetes mellitus prior to informed consent
2. Male and female patients on a diet and exercise regimen who are pre-treated with immediate release metformin or immediate release metformin plus sulfonylurea (see below for minimum doses). The treatment regimen has to be unchanged for 12 weeks prior to randomisation.

   Minimum dose for metformin: \> or = 1500 mg/day or maximum tolerated dose or maximum dose according to local label Minimum dose for sulfonylurea: \> or = half of the maximal recommended dose or maximum tolerated dose or maximum dose according to local label
3. HbA1c of \> or = 7.0% and \< or = 11% at Visit 1 (screening) in order to be eligible for randomised treatment HbA1c of \> 11% at Visit 1 (screening) in order to be eligible for the open-label treatment arm (25 mg BI 10773)
4. Age\> or = 18
5. Body Mass Index (BM)I \< or = 45 kg/m2 (Body Mass Index) at Visit 1 (Screening)
6. Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation

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. Any other antidiabetic drug within 12 weeks prior to randomisation except those mentioned in inclusion criterion 2
3. Myocardial infarction, stroke or transient ischemic attack (TIA) within 3 months prior to informed consent
4. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening and/or run-in phase
5. Impaired renal function, defined as eGFR\<30 ml/min (severe renal impairment) as determined during screening and/or run-in phase
6. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
7. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
8. Contraindications to metformin and/or sulfonylurea according to the local label for those patients that enter the study with the respective background therapy
9. Blood dyscrasias or any disorders causing haemolysis or unstable Red Blood Cell (e.g. malaria, babesiosis, haemolytic anaemia)
10. 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
11. 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 Typ 2 Diabetes
12. 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 (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if acceptable by local authorities), double barrier method and vasectomised partner
13. 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
14. Participation in another trial with an investigational drug within 30 days prior to informed consent
15. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial

Primary outcomes:
measure: HbA1c Change From Baseline
timeFrame: Baseline and 24 weeks
Secondary outcomes:
measure: Body Weight Change From Baseline
timeFrame: Baseline and 24 weeks
measure: Mean Daily Plasma Glucose (MDG) Change From Baseline
timeFrame: Baseline and 24 weeks
Other outcomes:
measure: Confirmed Hypoglycaemic Adverse Events
timeFrame: From first intake of randomised trial medication until 7 days after last trial medication intake, up to 231 days
Locations:
city: Birmingham
country: United States
facility: 1245.23.10145 Boehringer Ingelheim Investigational Site
state: Alabama
city: Tempe
country: United States
facility: 1245.23.10046 Boehringer Ingelheim Investigational Site
state: Arizona
city: Huntington Park
country: United States
facility: 1245.23.10095 Boehringer Ingelheim Investigational Site
state: California
city: Huntington Park
country: United States
facility: 1245.23.10109 Boehringer Ingelheim Investigational Site
state: California
city: Los Angeles
country: United States
facility: 1245.23.10074 Boehringer Ingelheim Investigational Site
state: California
city: Rancho Cucamonga
country: United States
facility: 1245.23.10149 Boehringer Ingelheim Investigational Site
state: California
city: Waterbury
country: United States
facility: 1245.23.10127 Boehringer Ingelheim Investigational Site
state: Connecticut
city: Fort Lauderdale
country: United States
facility: 1245.23.10042 Boehringer Ingelheim Investigational Site
state: Florida
city: Jupiter
country: United States
facility: 1245.23.10133 Boehringer Ingelheim Investigational Site
state: Florida
city: Decatur
country: United States
facility: 1245.23.10080 Boehringer Ingelheim Investigational Site
state: Georgia
city: Chicago
country: United States
facility: 1245.23.10001 Boehringer Ingelheim Investigational Site
state: Illinois
city: Des Moines
country: United States
facility: 1245.23.10159 Boehringer Ingelheim Investigational Site
state: Iowa
city: Arkansas City
country: United States
facility: 1245.23.10117 Boehringer Ingelheim Investigational Site
state: Kansas
city: Newton
country: United States
facility: 1245.23.10157 Boehringer Ingelheim Investigational Site
state: Kansas
city: Lexington
country: United States
facility: 1245.23.10148 Boehringer Ingelheim Investigational Site
state: Kentucky
city: Rochester
country: United States
facility: 1245.23.10034 Boehringer Ingelheim Investigational Site
state: New York
city: Smithtown
country: United States
facility: 1245.23.10123 Boehringer Ingelheim Investigational Site
state: New York
city: Columbus
country: United States
facility: 1245.23.10120 Boehringer Ingelheim Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: 1245.23.10031 Boehringer Ingelheim Investigational Site
state: Oklahoma
city: Mount Pleasant
country: United States
facility: 1245.23.10158 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Simpsonville
country: United States
facility: 1245.23.10015 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Houston
country: United States
facility: 1245.23.10156 Boehringer Ingelheim Investigational Site
state: Texas
city: Hurst
country: United States
facility: 1245.23.10153 Boehringer Ingelheim Investigational Site
state: Texas
city: Killeen
country: United States
facility: 1245.23.10143 Boehringer Ingelheim Investigational Site
state: Texas
city: San Antonio
country: United States
facility: 1245.23.10106 Boehringer Ingelheim Investigational Site
state: Texas
city: Calgary
country: Canada
facility: 1245.23.20032 Boehringer Ingelheim Investigational Site
state: Alberta
city: Edmonton
country: Canada
facility: 1245.23.20023 Boehringer Ingelheim Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: 1245.23.20028 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Victoria
country: Canada
facility: 1245.23.20033 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Paradise
country: Canada
facility: 1245.23.20024 Boehringer Ingelheim Investigational Site
state: Newfoundland and Labrador
city: St. John's
country: Canada
facility: 1245.23.20031 Boehringer Ingelheim Investigational Site
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: 1245.23.20026 Boehringer Ingelheim Investigational Site
state: Nova Scotia
city: Barrie
country: Canada
facility: 1245.23.20001 Boehringer Ingelheim Investigational Site
state: Ontario
city: Brampton
country: Canada
facility: 1245.23.20022 Boehringer Ingelheim Investigational Site
state: Ontario
city: Corunna
country: Canada
facility: 1245.23.20035 Boehringer Ingelheim Investigational Site
state: Ontario
city: Etobicoke
country: Canada
facility: 1245.23.20030 Boehringer Ingelheim Investigational Site
state: Ontario
city: Hamilton
country: Canada
facility: 1245.23.20037 Boehringer Ingelheim Investigational Site
state: Ontario
city: London
country: Canada
facility: 1245.23.20029 Boehringer Ingelheim Investigational Site
state: Ontario
city: Markham
country: Canada
facility: 1245.23.20003 Boehringer Ingelheim Investigational Site
state: Ontario
city: Oakville
country: Canada
facility: 1245.23.20040 Boehringer Ingelheim Investigational Site
state: Ontario
city: Sarnia
country: Canada
facility: 1245.23.20034 Boehringer Ingelheim Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: 1245.23.20039 Boehringer Ingelheim Investigational Site
state: Ontario
city: Laval
country: Canada
facility: 1245.23.20027 Boehringer Ingelheim Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: 1245.23.20025 Boehringer Ingelheim Investigational Site
state: Quebec
city: Sherbrooke
country: Canada
facility: 1245.23.20036 Boehringer Ingelheim Investigational Site
state: Quebec
city: Ville Saint-Laurent
country: Canada
facility: 1245.23.20038 Boehringer Ingelheim Investigational Site
state: Quebec
city: Beijing
country: China
facility: 1245.23.86031 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 1245.23.86032 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 1245.23.86033 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 1245.23.86034 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 1245.23.86035 Boehringer Ingelheim Investigational Site
city: Chengdu
country: China
facility: 1245.23.86048 Boehringer Ingelheim Investigational Site
city: Chongqing
country: China
facility: 1245.23.86058 Boehringer Ingelheim Investigational Site
city: Dalian
country: China
facility: 1245.23.86038 Boehringer Ingelheim Investigational Site
city: Guangzhou
country: China
facility: 1245.23.86002 Boehringer Ingelheim Investigational Site
city: Guangzhou
country: China
facility: 1245.23.86052 Boehringer Ingelheim Investigational Site
city: Haerbin
country: China
facility: 1245.23.86037 Boehringer Ingelheim Investigational Site
city: Jinan
country: China
facility: 1245.23.86049 Boehringer Ingelheim Investigational Site
city: Jinan
country: China
facility: 1245.23.86053 Boehringer Ingelheim Investigational Site
city: Nan Ning
country: China
facility: 1245.23.86055 Boehringer Ingelheim Investigational Site
city: Nan Ning
country: China
facility: 1245.23.86056 Boehringer Ingelheim Investigational Site
city: Nanjing
country: China
facility: 1245.23.86042 Boehringer Ingelheim Investigational Site
city: Nanjing
country: China
facility: 1245.23.86043 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 1245.23.86039 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 1245.23.86040 Boehringer Ingelheim Investigational Site
city: Shantou
country: China
facility: 1245.23.86054 Boehringer Ingelheim Investigational Site
city: Shenyang
country: China
facility: 1245.23.86057 Boehringer Ingelheim Investigational Site
city: Shijiazhuang
country: China
facility: 1245.23.86045 Boehringer Ingelheim Investigational Site
city: Suzhou
country: China
facility: 1245.23.86013 Boehringer Ingelheim Investigational Site
city: Tianjin
country: China
facility: 1245.23.86036 Boehringer Ingelheim Investigational Site
city: Xi'An
country: China
facility: 1245.23.86041 Boehringer Ingelheim Investigational Site
city: Zhenjiang
country: China
facility: 1245.23.86051 Boehringer Ingelheim Investigational Site
city: Arras
country: France
facility: 1245.23.33015 Boehringer Ingelheim Investigational Site
city: Bersée
country: France
facility: 1245.23.33008 Boehringer Ingelheim Investigational Site
city: Bischheim
country: France
facility: 1245.23.33020 Boehringer Ingelheim Investigational Site
city: Bondy Cedex
country: France
facility: 1245.23.33002 Boehringer Ingelheim Investigational Site
city: Bruay La Buissiere
country: France
facility: 1245.23.33016 Boehringer Ingelheim Investigational Site
city: Corbeil Essonnes
country: France
facility: 1245.23.33001 Boehringer Ingelheim Investigational Site
city: Croix
country: France
facility: 1245.23.33010 Boehringer Ingelheim Investigational Site
city: Hautmont
country: France
facility: 1245.23.33009 Boehringer Ingelheim Investigational Site
city: La Rochelle Cedex 1
country: France
facility: 1245.23.33003 Boehringer Ingelheim Investigational Site
city: Marseille
country: France
facility: 1245.23.33045 Boehringer Ingelheim Investigational Site
city: Mundolsheim
country: France
facility: 1245.23.33014 Boehringer Ingelheim Investigational Site
city: Narbonne Cedex
country: France
facility: 1245.23.33004 Boehringer Ingelheim Investigational Site
city: Schiltigheim
country: France
facility: 1245.23.33012 Boehringer Ingelheim Investigational Site
city: Strasbourg
country: France
facility: 1245.23.33013 Boehringer Ingelheim Investigational Site
city: Strasbourg
country: France
facility: 1245.23.33019 Boehringer Ingelheim Investigational Site
city: Vieux Condé
country: France
facility: 1245.23.33007 Boehringer Ingelheim Investigational Site
city: Wattrelos
country: France
facility: 1245.23.33018 Boehringer Ingelheim Investigational Site
city: Dormagen
country: Germany
facility: 1245.23.49001 Boehringer Ingelheim Investigational Site
city: Flörsheim
country: Germany
facility: 1245.23.49009 Boehringer Ingelheim Investigational Site
city: Hatten
country: Germany
facility: 1245.23.49004 Boehringer Ingelheim Investigational Site
city: Künzing
country: Germany
facility: 1245.23.49007 Boehringer Ingelheim Investigational Site
city: Neuwied
country: Germany
facility: 1245.23.49002 Boehringer Ingelheim Investigational Site
city: Nürnberg
country: Germany
facility: 1245.23.49008 Boehringer Ingelheim Investigational Site
city: Rednitzhembach
country: Germany
facility: 1245.23.49010 Boehringer Ingelheim Investigational Site
city: Rehburg-Loccum
country: Germany
facility: 1245.23.49006 Boehringer Ingelheim Investigational Site
city: Rehlingen-Siersburg
country: Germany
facility: 1245.23.49011 Boehringer Ingelheim Investigational Site
city: Saarbrücken
country: Germany
facility: 1245.23.49005 Boehringer Ingelheim Investigational Site
city: Unterschneidheim
country: Germany
facility: 1245.23.49003 Boehringer Ingelheim Investigational Site
city: Coimbatore
country: India
facility: 1245.23.91101 Boehringer Ingelheim Investigational Site
city: Indore
country: India
facility: 1245.23.91104 Boehringer Ingelheim Investigational Site
city: Maharashtra
country: India
facility: 1245.23.91103 Boehringer Ingelheim Investigational Site
city: Nagpur
country: India
facility: 1245.23.91102 Boehringer Ingelheim Investigational Site
city: Pune
country: India
facility: 1245.23.91105 Boehringer Ingelheim Investigational Site
city: Anyang
country: Korea, Republic of
facility: 1245.23.82012 Boehringer Ingelheim Investigational Site
city: Busan
country: Korea, Republic of
facility: 1245.23.82004 Boehringer Ingelheim Investigational Site
city: Goyang
country: Korea, Republic of
facility: 1245.23.82011 Boehringer Ingelheim Investigational Site
city: Ilsan
country: Korea, Republic of
facility: 1245.23.82009 Boehringer Ingelheim Investigational Site
city: Incheon
country: Korea, Republic of
facility: 1245.23.82001 Boehringer Ingelheim Investigational Site
city: Jeonju
country: Korea, Republic of
facility: 1245.23.82006 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1245.23.82005 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1245.23.82007 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1245.23.82008 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1245.23.82010 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1245.23.82014 Boehringer Ingelheim Investigational Site
city: Suwon
country: Korea, Republic of
facility: 1245.23.82002 Boehringer Ingelheim Investigational Site
city: Wonju
country: Korea, Republic of
facility: 1245.23.82003 Boehringer Ingelheim Investigational Site
city: Guadalajara
country: Mexico
facility: 1245.23.52003 Boehringer Ingelheim Investigational Site
city: Guadalajara
country: Mexico
facility: 1245.23.52004 Boehringer Ingelheim Investigational Site
city: Monterrey
country: Mexico
facility: 1245.23.52001 Boehringer Ingelheim Investigational Site
city: Monterrey
country: Mexico
facility: 1245.23.52002 Boehringer Ingelheim Investigational Site
city: Bratislava
country: Slovakia
facility: 1245.23.74005 Boehringer Ingelheim Investigational Site
city: Lucenec
country: Slovakia
facility: 1245.23.74002 Boehringer Ingelheim Investigational Site
city: Nitra
country: Slovakia
facility: 1245.23.74006 Boehringer Ingelheim Investigational Site
city: Nove Zamky
country: Slovakia
facility: 1245.23.74014 Boehringer Ingelheim Investigational Site
city: Povazska Bystrica
country: Slovakia
facility: 1245.23.74001 Boehringer Ingelheim Investigational Site
city: Presov
country: Slovakia
facility: 1245.23.74004 Boehringer Ingelheim Investigational Site
city: Trebisov
country: Slovakia
facility: 1245.23.74003 Boehringer Ingelheim Investigational Site
city: Celje
country: Slovenia
facility: 1245.23.38003 Boehringer Ingelheim Investigational Site
city: Koper
country: Slovenia
facility: 1245.23.38002 Boehringer Ingelheim Investigational Site
city: Maribor
country: Slovenia
facility: 1245.23.38001 Boehringer Ingelheim Investigational Site
city: Kaohsiung
country: Taiwan
facility: 1245.23.88010 Boehringer Ingelheim Investigational Site
city: Kaohsiung
country: Taiwan
facility: 1245.23.88011 Boehringer Ingelheim Investigational Site
city: Kaohsiung
country: Taiwan
facility: 1245.23.88012 Boehringer Ingelheim Investigational Site
city: Kaohsiung
country: Taiwan
facility: 1245.23.88013 Boehringer Ingelheim Investigational Site
city: Taichung
country: Taiwan
facility: 1245.23.88009 Boehringer Ingelheim Investigational Site
city: Tainan
country: Taiwan
facility: 1245.23.88014 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1245.23.88006 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1245.23.88007 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1245.23.88021 Boehringer Ingelheim Investigational Site
city: Taoyuan County
country: Taiwan
facility: 1245.23.88008 Boehringer Ingelheim Investigational Site
city: Erzurum
country: Turkey
facility: 1245.23.90003 Boehringer Ingelheim Investigational Site
city: Gaziantep
country: Turkey
facility: 1245.23.90001 Boehringer Ingelheim Investigational Site
city: Istanbul
country: Turkey
facility: 1245.23.90002 Boehringer Ingelheim Investigational Site
city: Istanbul
country: Turkey
facility: 1245.23.90006 Boehringer Ingelheim Investigational Site
city: Istanbul
country: Turkey
facility: 1245.23.90007 Boehringer Ingelheim Investigational Site
city: Izmir
country: Turkey
facility: 1245.23.90004 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Tuttle KR, Levin A, Nangaku M, Kadowaki T, Agarwal R, Hauske SJ, Elsasser A, Ritter I, Steubl D, Wanner C, Wheeler DC. Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials. Diabetes Care. 2022 Jun 2;45(6):1445-1452. doi: 10.2337/dc21-2034.
citation: Inzucchi SE, Davies MJ, Khunti K, Trivedi P, George JT, Zwiener I, Johansen OE, Sattar N. Empagliflozin treatment effects across categories of baseline HbA1c, body weight and blood pressure as an add-on to metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2021 Feb;23(2):425-433. doi: 10.1111/dom.14234. Epub 2020 Nov 20.
citation: Cherney D, Lund SS, Perkins BA, Groop PH, Cooper ME, Kaspers S, Pfarr E, Woerle HJ, von Eynatten M. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016 Sep;59(9):1860-70. doi: 10.1007/s00125-016-4008-2. Epub 2016 Jun 17.
citation: Haring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Woerle HJ, Broedl UC; EMPA-REG METSU Trial Investigators. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013 Nov;36(11):3396-404. doi: 10.2337/dc12-2673. Epub 2013 Aug 20.