Clinical trial NCT00602472: BI 1356 (Linagliptin) in Combination With Metformin and a Sulphonylurea in Type 2 Diabetes
Official title: A Randomised, Double-blind, Placebo-controlled Parallel Group Efficacy and Safety Study of BI 1356 (5 mg) Administered Orally Once Daily Over 24 Weeks, With an Open-label Extension to One Year (Placebo Patients Switched to BI 1356), in Type 2 Diabetic Patients With Insufficient Glycaemic Control Despite a Therapy of Metformin in Combination With a Sulphonylurea
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2008-01-28
Enrollment: 1058
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
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 BI 1356 (5 mg once daily) compared to placebo given for 24 weeks as add-on therapy to metformin in combination with a sulphonylurea in patients with type 2 diabetes mellitus with insufficient glycaemic control.


Eligibility criteria: Inclusion criteria:

1. Male and female patients with a diagnosis of type 2 diabetes mellitus, currently treated only with a stable total daily dose of preferably\* \>/= 1500 mg metformin and a dose of a sulphonylurea drug that has been documented, by the Investigator, to be the individual maximum tolerated dose of that sulphonylurea drug. Both the dose and dosing regimen of metformin and the sulphonylurea must be stable (i.e. unchanged) for 10 weeks prior to informed consent, and must not be changed for the duration of the trial
2. Glycosylated haemoglobin A1 (HbA1c) \>/= 7.0 and \</= 10.0% at the screening Visit 1a and at Visit 2 (start of placebo run-in phase)
3. Age \>/= 18 and \</= 80 years at Visit 1a (screening)
4. BMI (Body Mass Index) \</= 40 kg/m2 at Visit 1a (screening)
5. Signed and dated written informed consent, at the latest by the date of Visit 1a, in accordance with GCP and local legislation \*Patients currently treated with a total daily dose of less than 1500 mg metformin can be included in the trial if the Investigator has documented that the dose is the maximum tolerated dose of metformin for that patient.

Exclusion criteria:

1. Myocardial infarction, stroke or TIA (transient ischaemic attack) within 6 months prior to the date of informed consent
2. Impaired hepatic function, defined by serum levels of either alanine transaminase (ALT/SGPT), aspartase transaminase (AST/SGOT), or alkaline phosphatase (ALP) above 3 times the upper limit of normal (ULN), as determined at Visit 1a
3. Renal failure or renal impairment (serum creatinine \>/= 1.5 mg/dl) as determined at Visit 1a
4. Treatment with rosiglitazone or pioglitazone within 3 months prior to the date of informed consent
5. Treatment with GLP-1 analogues (e.g. exenatide) within 3 months prior to the date of informed consent
6. Treatment with insulin within 3 months prior to the date of informed consent
7. Treatment with anti-obesity drugs (e.g. sibutramine, rimonabant, orlistat) within 3 months prior to the date of informed consent
8. Current treatment with systemic steroids (i.e. at the time of informed consent) or a change in the dosage of thyroid hormones within 6 weeks prior to the date of informed consent
9. Pre-menopausal women (last menstruation \</= 1 year prior to the date of 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 periodic pregnancy testing during their participation in the trial. Acceptable methods of birth control include transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence and vasectomised partner. No exception will be made.
10. Known hypersensitivity or allergy to the investigational product or its excipients or to the trial background therapy (i.e. metformin in combination with a sulphonylurea) or sulphonamides
11. Dehydration (as confirmed by the Investigators clinical opinion)
12. Current acute or chronic metabolic acidosis

Primary outcomes:
measure: HbA1c Change From Baseline to Week 24
timeFrame: Baseline and week 24
Secondary outcomes:
measure: HbA1c Change From Baseline to Week 6
timeFrame: Baseline and week 6
measure: HbA1c Change From Baseline to Week 12
timeFrame: Baseline and week 12
measure: HbA1c Change From Baseline to Week 18
timeFrame: Baseline and week 18
measure: FPG Change From Baseline to Week 24
timeFrame: Baseline and week 24
measure: FPG Change From Baseline to Week 6
timeFrame: Baseline and week 6
measure: FPG Change From Baseline to Week 12
timeFrame: Baseline and week 12
measure: FPG Change From Baseline to Week 18
timeFrame: Baseline and week 18
measure: Percentage of Patients With HbA1c <7.0% at Week 24
timeFrame: Baseline and week 24
measure: Percentage of Patients With HbA1c < 7.0% at Week 24
timeFrame: Baseline and week 24
measure: Percentage of Patients With HbA1c <6.5% at Week 24
timeFrame: Baseline and week 24
measure: Percentage of Patients With HbA1c<6.5% at Week 24
timeFrame: Baseline and week 24
measure: Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24
timeFrame: Baseline and week 24
Other outcomes:
Locations:
city: Capital Federal
country: Argentina
facility: 1218.18.54001 Boehringer Ingelheim Investigational Site
city: Capital Federal
country: Argentina
facility: 1218.18.54002 Boehringer Ingelheim Investigational Site
city: Capital Federal
country: Argentina
facility: 1218.18.54004 Boehringer Ingelheim Investigational Site
city: Capital Federal
country: Argentina
facility: 1218.18.54005 Boehringer Ingelheim Investigational Site
city: Capital Federal
country: Argentina
facility: 1218.18.54010 Boehringer Ingelheim Investigational Site
city: Corrientes
country: Argentina
facility: 1218.18.54014 Boehringer Ingelheim Investigational Site
city: Córdoba
country: Argentina
facility: 1218.18.54009 Boehringer Ingelheim Investigational Site
city: Córdoba
country: Argentina
facility: 1218.18.54013 Boehringer Ingelheim Investigational Site
city: Mar del Plata
country: Argentina
facility: 1218.18.54003 Boehringer Ingelheim Investigational Site
city: Mar del Plata
country: Argentina
facility: 1218.18.54012 Boehringer Ingelheim Investigational Site
city: Mendoza
country: Argentina
facility: 1218.18.54011 Boehringer Ingelheim Investigational Site
city: Parque Velez Sarfield
country: Argentina
facility: 1218.18.54015 Boehringer Ingelheim Investigational Site
city: Rosario
country: Argentina
facility: 1218.18.54006 Boehringer Ingelheim Investigational Site
city: Salta
country: Argentina
facility: 1218.18.54007 Boehringer Ingelheim Investigational Site
city: Brugge
country: Belgium
facility: 1218.18.32005 Boehringer Ingelheim Investigational Site
city: Brussel
country: Belgium
facility: 1218.18.32007 Boehringer Ingelheim Investigational Site
city: Edegem
country: Belgium
facility: 1218.18.32006 Boehringer Ingelheim Investigational Site
city: Genk
country: Belgium
facility: 1218.18.32004 Boehringer Ingelheim Investigational Site
city: Gent
country: Belgium
facility: 1218.18.32003 Boehringer Ingelheim Investigational Site
city: Huy
country: Belgium
facility: 1218.18.32002 Boehringer Ingelheim Investigational Site
city: Liège
country: Belgium
facility: 1218.18.32001 Boehringer Ingelheim Investigational Site
city: Calgary
country: Canada
facility: 1218.18.01005 Boehringer Ingelheim Investigational Site
state: Alberta
city: Calgary
country: Canada
facility: 1218.18.01010 Boehringer Ingelheim Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: 1218.18.01003 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Vancouver
country: Canada
facility: 1218.18.01011 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Etobicoke
country: Canada
facility: 1218.18.01006 Boehringer Ingelheim Investigational Site
state: Ontario
city: Hamilton
country: Canada
facility: 1218.18.01009 Boehringer Ingelheim Investigational Site
state: Ontario
city: London
country: Canada
facility: 1218.18.01002 Boehringer Ingelheim Investigational Site
state: Ontario
city: Oakville
country: Canada
facility: 1218.18.01012 Boehringer Ingelheim Investigational Site
state: Ontario
city: Sarnia
country: Canada
facility: 1218.18.01008 Boehringer Ingelheim Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: 1218.18.01001 Boehringer Ingelheim Investigational Site
state: Ontario
city: Montague
country: Canada
facility: 1218.18.01004 Boehringer Ingelheim Investigational Site
state: Prince Edward Island
city: Saskatoon
country: Canada
facility: 1218.18.01007 Boehringer Ingelheim Investigational Site
state: Saskatchewan
city: Beijing
country: China
facility: 1218.18.86001 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 1218.18.86002 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 1218.18.86004 Boehringer Ingelheim Investigational Site
city: Chengdu, Sichuan Province
country: China
facility: 1218.18.86013 Boehringer Ingelheim Investigational Site
city: Dalian
country: China
facility: 1218.18.86009 Boehringer Ingelheim Investigational Site
city: Guangzhou
country: China
facility: 1218.18.86011 Boehringer Ingelheim Investigational Site
city: Haerbin
country: China
facility: 1218.18.86014 Boehringer Ingelheim Investigational Site
city: Nanjing, Jiangsu Province
country: China
facility: 1218.18.86005 Boehringer Ingelheim Investigational Site
city: Qingdao
country: China
facility: 1218.18.86008 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 1218.18.86015 Boehringer Ingelheim Investigational Site
city: Shen Yang
country: China
facility: 1218.18.86010 Boehringer Ingelheim Investigational Site
city: Weizikeng
country: China
facility: 1218.18.86003 Boehringer Ingelheim Investigational Site
city: Wuhan, Hubei Province
country: China
facility: 1218.18.86012 Boehringer Ingelheim Investigational Site
city: Wuhan
country: China
facility: 1218.18.86007 Boehringer Ingelheim Investigational Site
city: Xian, Shanxi Province
country: China
facility: 1218.18.86006 Boehringer Ingelheim Investigational Site
city: Aschaffenburg
country: Germany
facility: 1218.18.49004 Boehringer Ingelheim Investigational Site
city: Bad Mergentheim
country: Germany
facility: 1218.18.49028 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1218.18.49022 Boehringer Ingelheim Investigational Site
city: Bosenheim
country: Germany
facility: 1218.18.49024 Boehringer Ingelheim Investigational Site
city: Dresden
country: Germany
facility: 1218.18.49020 Boehringer Ingelheim Investigational Site
city: Mainz
country: Germany
facility: 1218.18.49101 Boehringer Ingelheim Investigational Site
city: Neuwied
country: Germany
facility: 1218.18.49003 Boehringer Ingelheim Investigational Site
city: Nürnberg
country: Germany
facility: 1218.18.49007 Boehringer Ingelheim Investigational Site
city: Saarbrücken
country: Germany
facility: 1218.18.49014 Boehringer Ingelheim Investigational Site
city: Busan
country: Korea, Republic of
facility: 1218.18.82004 Boehringer Ingelheim Investigational Site
city: Daegu
country: Korea, Republic of
facility: 1218.18.82011 Boehringer Ingelheim Investigational Site
city: Incheon
country: Korea, Republic of
facility: 1218.18.82008 Boehringer Ingelheim Investigational Site
city: Jeonju
country: Korea, Republic of
facility: 1218.18.82010 Boehringer Ingelheim Investigational Site
city: Pusan
country: Korea, Republic of
facility: 1218.18.82002 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1218.18.82001 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1218.18.82005 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1218.18.82006 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1218.18.82007 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1218.18.82009 Boehringer Ingelheim Investigational Site
city: Suwon
country: Korea, Republic of
facility: 1218.18.82003 Boehringer Ingelheim Investigational Site
city: Manila
country: Philippines
facility: 1218.18.63005 Boehringer Ingelheim Investigational Site
city: Marikina
country: Philippines
facility: 1218.18.63002 Boehringer Ingelheim Investigational Site
city: Pasig
country: Philippines
facility: 1218.18.63001 Boehringer Ingelheim Investigational Site
city: Quezon City
country: Philippines
facility: 1218.18.63004 Boehringer Ingelheim Investigational Site
city: San Juan
country: Philippines
facility: 1218.18.63003 Boehringer Ingelheim Investigational Site
city: Arkhangelsk
country: Russian Federation
facility: 1218.18.70014 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 1218.18.70012 Boehringer Ingelheim Investigational Site
city: Rostov-on-Don
country: Russian Federation
facility: 1218.18.70013 Boehringer Ingelheim Investigational Site
city: Samara
country: Russian Federation
facility: 1218.18.70016 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 1218.18.70015 Boehringer Ingelheim Investigational Site
city: Changhua
country: Taiwan
facility: 1218.18.88605 Boehringer Ingelheim Investigational Site
city: Taichung
country: Taiwan
facility: 1218.18.88604 Boehringer Ingelheim Investigational Site
city: Tainan
country: Taiwan
facility: 1218.18.88606 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1218.18.88601 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1218.18.88602 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1218.18.88603 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1218.18.88607 Boehringer Ingelheim Investigational Site
city: Taoyuan
country: Taiwan
facility: 1218.18.88608 Boehringer Ingelheim Investigational Site
city: Erzurum
country: Turkey
facility: 1218.18.90003 Boehringer Ingelheim Investigational Site
city: Istanbul
country: Turkey
facility: 1218.18.90005 Boehringer Ingelheim Investigational Site
city: Izmir
country: Turkey
facility: 1218.18.90001 Boehringer Ingelheim Investigational Site
city: Konya
country: Turkey
facility: 1218.18.90004 Boehringer Ingelheim Investigational Site
city: Ashford
country: United Kingdom
facility: 1218.18.44005 Boehringer Ingelheim Investigational Site
city: Baillieston, Glasgow
country: United Kingdom
facility: 1218.18.44004 Boehringer Ingelheim Investigational Site
city: Bath
country: United Kingdom
facility: 1218.18.44001 Boehringer Ingelheim Investigational Site
city: Burbage
country: United Kingdom
facility: 1218.18.44003 Boehringer Ingelheim Investigational Site
city: Bury St Edmonds
country: United Kingdom
facility: 1218.18.44010 Boehringer Ingelheim Investigational Site
city: Cardiff
country: United Kingdom
facility: 1218.18.44009 Boehringer Ingelheim Investigational Site
city: Glasgow
country: United Kingdom
facility: 1218.18.44008 Boehringer Ingelheim Investigational Site
city: Penarth
country: United Kingdom
facility: 1218.18.44002 Boehringer Ingelheim Investigational Site
city: Reading
country: United Kingdom
facility: 1218.18.44006 Boehringer Ingelheim Investigational Site
city: Waterloo, Liverpool
country: United Kingdom
facility: 1218.18.44007 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Del Prato S, Patel S, Crowe S, von Eynatten M. Efficacy and safety of linagliptin according to patient baseline characteristics: A pooled analysis of three phase 3 trials. Nutr Metab Cardiovasc Dis. 2016 Oct;26(10):886-92. doi: 10.1016/j.numecd.2016.06.015. Epub 2016 Jul 1.
citation: Zeng Z, Yang JK, Tong N, Yan S, Zhang X, Gong Y, Woerle HJ. Efficacy and safety of linagliptin added to metformin and sulphonylurea in Chinese patients with type 2 diabetes: a sub-analysis of data from a randomised clinical trial. Curr Med Res Opin. 2013 Aug;29(8):921-9. doi: 10.1185/03007995.2013.805123. Epub 2013 Jun 4.
citation: Johansen OE, Neubacher D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012 Jan 10;11:3. doi: 10.1186/1475-2840-11-3.
citation: Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011 Nov;28(11):1352-61. doi: 10.1111/j.1464-5491.2011.03387.x.