Efficacy and Safety of BI 1356 in Combination With Metformin in Patients With Type 2 Diabetes

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Boehringer Ingelheim Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT00622284

First received: February 13, 2008

Last updated: November 30, 2012

Last verified: November 2012

History of Changes

Results First Received: November 30, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double-Blind; Primary Purpose: Treatment
Condition:	Diabetes Mellitus, Type 2
Interventions:	Drug: Placebo identical to BI 1356 5mg Drug: Placebo identical to Glimepiride 1mg or 2mg or 3mg or 4 mg Drug: BI 1356 Drug: Glimepiride

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
There were in total 1560 patients randomised in the study. Of these, 1 patient was not treated. The remaining 8 patients not accounted for in the treated set were removed from all study analyses (explained in trial report) due to major good-clinical-practice violations at the site, and the inability to verify the validity of any patient level data.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Linagliptin	Patients randomized to receive Linagliptin 5mg and metformin
Glimepiride	Patients randomized to receive Glimepiride 1-4mg and metformin

Participant Flow: Overall Study

	Linagliptin	Glimepiride
STARTED	776 ^[1]	775 ^[2]
COMPLETED	587 ^[3]	604 ^[3]
NOT COMPLETED	189	171
Lack of Efficacy	45	15
Adverse Event	61	90
Protocol Violation	12	5
Lost to Follow-up	11	13
Withdrawal by Subject	27	24
Other reason (not specified)	33	24

[1]	Number who started treatment. One patient in the Linagliptin group was randomized but not treated.
[2]	Number who started treatment.
[3]	Number who completed treatment.

Baseline Characteristics

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Reporting Groups

	Description
Linagliptin	Patients randomized to receive Linagliptin 5mg and metformin
Glimepiride	Patients randomized to receive Glimepiride 1-4mg and metformin
Total	Total of all reporting groups

Baseline Measures

	Linagliptin	Glimepiride	Total
Number of Participants [units: participants]	776	775	1551
Age [units: Years] Mean ± Standard Deviation	59.8 ± 9.4	59.8 ± 9.4	59.8 ± 9.4
Gender [units: Patients]
Female	314	304	618
Male	462	471	933
Body mass index (BMI) continuous [units: kg/m^2] Mean ± Standard Deviation	30.21 ± 4.77	30.31 ± 4.57	30.26 ± 4.67
Weight [units: kg] Mean ± Standard Deviation	86.14 ± 17.57	86.77 ± 16.69	86.46 ± 17.14
Glycosylated haemoglobin (HbA1c) ^[1] [units: Percent] Mean ± Standard Deviation	7.69 ± 0.88	7.69 ± 0.86	7.69 ± 0.87
Fasting blood plasma glucose (FPG) ^[2] [units: mg/dL] Mean ± Standard Deviation	164.46 ± 42.83	166.09 ± 42.05	165.27 ± 42.43

[1]	Baseline HbA1c was available for 1519 patients in the Full Analysis Set (FAS), 764 treated with Linagliptin and 755 patients treated with Glimepiride.
[2]	Baseline fasting plasma glucose (FPG) was available for 1475 patients in the FAS, 740 treated with Linagliptin and 735 patients treated with Glimepiride.

Outcome Measures

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1. Primary:

HbA1c Change From Baseline at Week 52 [ Time Frame: Baseline and week 52 ]

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2. Primary:

HbA1c Change From Baseline at Week 104 [ Time Frame: Baseline and week 104 ]

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3. Secondary:

Body Weight Change From Baseline at Week 52 [ Time Frame: Baseline and week 52 ]

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4. Secondary:

Body Weight Change From Baseline at Week 104 [ Time Frame: Baseline and week 104 ]

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5. Secondary:

Incidence of Hypoglycaemic Events up to 52 Weeks [ Time Frame: Week 52 ]

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6. Secondary:

Incidence of Hypoglycaemic Events up to 104 Weeks [ Time Frame: Week 104 ]

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7. Secondary:

Fasting Plasma Glucose (FPG) Change From Baseline at Week 52 [ Time Frame: Baseline and week 52 ]

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8. Secondary:

Fasting Plasma Glucose (FPG) Change From Baseline at Week 104 [ Time Frame: Baseline and week 104 ]

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9. Secondary:

Percentage of Patients With HbA1c <7.0% at Week 52 [ Time Frame: Week 52 ]

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10. Secondary:

Percentage of Patients With HbA1c <7.0% at Week 104 [ Time Frame: Week 104 ]

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11. Secondary:

Percentage of Patients With HbA1c <6.5% at Week 52 [ Time Frame: Week 52 ]

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12. Secondary:

Percentage of Patients With HbA1c <6.5% at Week 104 [ Time Frame: Week 104 ]

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13. Secondary:

Percentage of Patients With HbA1c Lowering by 0.5% at Week 104 [ Time Frame: Week 104 ]

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14. Secondary:

2 hr Postprandial Glucose (PPG) Change From Baseline at Week 104 [ Time Frame: Baseline and week 104 ]

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15. Secondary:

HbA1c Change at Week 4 [ Time Frame: Baseline and week 4 ]

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16. Secondary:

HbA1c Change at Week 8 [ Time Frame: Baseline and week 8 ]

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17. Secondary:

HbA1c Change at Week 12 [ Time Frame: Baseline and week 12 ]

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18. Secondary:

HbA1c Change at Week 16 [ Time Frame: Baseline and week 16 ]

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19. Secondary:

HbA1c Change at Week 28 [ Time Frame: Baseline and week 28 ]

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20. Secondary:

HbA1c Change at Week 40 [ Time Frame: Baseline and week 40 ]

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21. Secondary:

HbA1c Change at Week 52 [ Time Frame: Baseline and week 52 ]

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22. Secondary:

HbA1c Change at Week 65 [ Time Frame: Baseline and week 65 ]

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23. Secondary:

HbA1c Change at Week 78 [ Time Frame: Baseline and week 78 ]

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24. Secondary:

HbA1c Change at Week 91 [ Time Frame: Baseline and week 91 ]

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25. Secondary:

HbA1c Change at Week 104 [ Time Frame: Baseline and week 104 ]

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26. Secondary:

Change in Baseline Lipid Parameter Cholesterol at Week 104 [ Time Frame: Baseline and week 104 ]

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27. Secondary:

Change in Baseline Lipid Parameter HDL at Week 104 [ Time Frame: Baseline and week 104 ]

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28. Secondary:

Change in Baseline Lipid Parameter Low Density Lipoprotein (LDL) at Week 104 [ Time Frame: Baseline and week 104 ]

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29. Secondary:

Change in Baseline Lipid Parameter Triglyceride at Week 104 [ Time Frame: Baseline and week 104 ]

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Serious Adverse Events

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Other Adverse Events

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Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Linagliptin	Patients randomized to receive Linagliptin 5mg and metformin
Glimepiride	Patients randomized to receive Glimepiride 1-4mg and metformin

Other Adverse Events

	Linagliptin	Glimepiride
Total, other (not including serious) adverse events
# participants affected / at risk	438/776	526/775
Gastrointestinal disorders
Diarrhoea ^†
# participants affected / at risk	52/776 (6.70%)	60/775 (7.74%)
Nausea ^†
# participants affected / at risk	37/776 (4.77%)	39/775 (5.03%)
Infections and infestations
Bronchitis ^†
# participants affected / at risk	50/776 (6.44%)	60/775 (7.74%)
Nasopharyngitis ^†
# participants affected / at risk	124/776 (15.98%)	125/775 (16.13%)
Upper respiratory tract infection ^†
# participants affected / at risk	62/776 (7.99%)	59/775 (7.61%)
Urinary tract infection ^†
# participants affected / at risk	49/776 (6.31%)	51/775 (6.58%)
Metabolism and nutrition disorders
Hyperglycaemia ^†
# participants affected / at risk	39/776 (5.03%)	40/775 (5.16%)
Hypoglycaemia ^†
# participants affected / at risk	55/776 (7.09%)	267/775 (34.45%)
Musculoskeletal and connective tissue disorders
Arthralgia ^†
# participants affected / at risk	60/776 (7.73%)	45/775 (5.81%)
Back pain ^†
# participants affected / at risk	68/776 (8.76%)	65/775 (8.39%)
Pain in extremity ^†
# participants affected / at risk	41/776 (5.28%)	30/775 (3.87%)
Nervous system disorders
Dizziness ^†
# participants affected / at risk	26/776 (3.35%)	47/775 (6.06%)
Headache ^†
# participants affected / at risk	50/776 (6.44%)	40/775 (5.16%)
Respiratory, thoracic and mediastinal disorders
Cough ^†
# participants affected / at risk	47/776 (6.06%)	38/775 (4.90%)
Vascular disorders
Hypertension ^†
# participants affected / at risk	48/776 (6.19%)	60/775 (7.74%)

†	Events were collected by systematic assessment

More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
With the exception of HbA1c<6.5% and HbA1c<7.0% at Week52, all other endpoints are presented in the Week52 repeated analysis within the final clinical trial report, where discrepancies between interim and final results are also explained.

Results Point of Contact:

Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
phone: 1-800-243-0127
e-mail: clintriage.rdg@boehringer-ingelheim.com

No publications provided by Boehringer Ingelheim Pharmaceuticals

Publications automatically indexed to this study:

Gallwitz B, Rosenstock J, Emser A, von Eynatten M, Woerle HJ. Linagliptin is more effective than glimepiride at achieving a composite outcome of target HbA₁c < 7% with no hypoglycaemia and no weight gain over 2 years. Int J Clin Pract. 2013 Apr;67(4):317-21. doi: 10.1111/ijcp.12101.

Gallwitz B, Rosenstock J, Rauch T, Bhattacharya S, Patel S, von Eynatten M, Dugi KA, Woerle HJ. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet. 2012 Aug 4;380(9840):475-83. Epub 2012 Jun 28.

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.

Responsible Party:	Boehringer Ingelheim Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00622284 History of Changes
Other Study ID Numbers:	1218.20, 2007-004585-40
Study First Received:	February 13, 2008
Results First Received:	November 30, 2011
Last Updated:	November 30, 2012
Health Authority:	Bulgaria: Bulgarian Drug Agency, BG-1504 Sofia Denmark: Danish Medicines Agency France: AFSSAPS 143/147, bld Anatole France 93285 Saint-Denis Cedex FRANCE Germany: Federal Institute for Drugs and Medical Devices Great Britain: MHRA Hong Kong: Department of Health Hungary: National Institute of Pharmacy, H-1051 Budapest India: Drugs Controller General of India Ireland: Irish Medicines Board Italy: Comitato Etico Locale per la Sperimentazione Clinica dei Medicinali A.O. Universitaria Senese - Località Le Scotte - SIENA Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) Norway: Norwegian Medicines Agency (Statens Legemiddelverk) Poland: Registration Medicinal Product Medical Device Biocidal Product South Africa: Medicines Control Council Sweden: Sweden; Läkemedelsverket (Medical Product Agency) United States: Food and Drug Administration

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