Efficacy and Safety of B I1356 (Linagliptin) vs. Placebo... | NCT00601250

ID	Type	Description	Link
2007-002457-24	EudraCT Number	EudraCT

Label	Type	Description	Intervention Names
Linagliptin	Experimental	Patients receive linagliptin 5 mg tablets once daily	Drug: linagliptin
Placebo	Placebo Comparator	Patients receive placebo tablets matching linagliptin 5 mg tablets once daily	Drug: linagliptin

Name	Type	Description	Arm Group Labels	Other Names
linagliptin	Drug	Patients receive linagliptin 5 mg tablets once daily	Placebo

Measure	Description	Time Frame
HbA1c Change From Baseline at Week 24	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.	Baseline and week 24

Measure	Description	Time Frame
HbA1c Change From Baseline at Week 6	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.	Baseline and week 6
HbA1c Change From Baseline at Week 12

Eligibility Module

Eligibility Criteria

Inclusion criteria:

Male and female patients with a diagnosis of type 2 diabetes mellitus and previously treated with metformin alone, or with metformin and not more than one other oral antidiabetic drug
Diagnosis of type 2 diabetes prior to informed consent
Glycosylated haemoglobin A1 (HbA1c)at screening:

For patients undergoing wash out of previous medication: HbA1c 6.5 - 9.0% For patients not undergoing wash-out of previous medication: HbA1c 7.0 - 10.0%
Glycosylated haemoglobin A1 (HbA1c) 7.0 - 10.0% at the beginning of Placebo Run-in
Age 18 -80 years
BMI (Body Mass Index) less than 40 kg/m2
Signed and dated written informed consent by date of Visit 1a in accordance with GCP and local legislation

Exclusion criteria:

Myocardial infarction, stroke or transient ischemic attack (TIA) within 6 months prior to informed consent
Impaired hepatic function
Known hypersensitivity or allergy to the investigational product or its excipients or metformin or placebo
Treatment with rosiglitazone or pioglitazone within 3 months prior to informed consent
Treatment with an injectable GLP-1 analogue (e.g. exenatide) within 3 months prior to informed consent
Treatment with insulin within 3 months prior to informed consent
Treatment with anti-obesity drugs (e.g. sibutramine, orlistat, rimonabant) within 3 months prior to informed consent
Alcohol abuse within the 3 months prior to informed consent that would interfere with trial participation or drug abuse
Participation in another trial with an investigational drug within 2 months prior to informed consent
Pre-menopausal women 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.
Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent.
Renal failure or renal impairment
Unstable or acute congestive heart failure
Acute or chronic metabolic acidosis (present in patient history)
Hereditary galactose intolerance

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
1218.17.10003 Boehringer Ingelheim Investigational Site		Chula Vista	California		United States
1218.17.10014 Boehringer Ingelheim Investigational Site

PubMed Identifier	Type	Citation	Retractions
27484756	Derived	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.

ID	Title	Description
FG000	Placebo	Patients randomized to receive treatment with matching placebo
FG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

HbA1c Change From Baseline at Week 24

HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available. Last observation carried forward (LOCF) was used as the imputation rule.

Posted

Mean

Standard Error

Percent

Baseline and week 24

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000175 OG001513

Title

Denominators

Categories

Title	Measurements
	OG0000.15± 0.06 OG001-0.49± 0.04

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Linagliptin vs. Placebo	ANCOVA		<0.0001		Least Squares Mean Difference	-0.64	Standard Error of the Mean	0.07	2-Sided	95	-0.78	-0.5				No	Superiority or Other

Secondary

HbA1c Change From Baseline at Week 6

HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

Posted

Mean

Standard Error

Percent

Baseline and week 6

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

HbA1c Change From Baseline at Week 12

HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

Posted

Mean

Standard Error

Percent

Baseline and week 12

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

HbA1c Change From Baseline at Week 18

HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

Posted

Mean

Standard Error

Percent

Baseline and week 18

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

FPG Change From Baseline at Week 24

This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

Posted

Mean

Standard Error

mg/dL

Baseline and week 24

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

FPG Change From Baseline at Week 6

This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

Posted

Mean

Standard Error

mg/dL

Baseline and week 6

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

FPG Change From Baseline at Week 12

This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

Posted

Mean

Standard Error

mg/dL

Baseline and week 12

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

FPG Change From Baseline at Week 18

This change from baseline reflects the Week 18 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

Posted

Mean

Standard Error

mg/dL

Baseline and week 18

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

Percentage of Patients With HbA1c <7.0% at Week 24.

The percentage of patients with an HbA1c value below 7.0% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 7.0%. Only patients with baseline HbA1c >= 7%

This population includes the FAS with baseline HbA1c >= 7.0%. Non-completers were considered as failure imputation (NCF).

Posted

Number

percentage of patients

Baseline and week 24

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

Percentage of Patients With HbA1c < 7.0% at Week 24

This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).

Posted

Number

percentage of patients

Baseline and week 24

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

Percentage of Patients With HbA1c <6.5% at Week 24

The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c >= 6.5%. Only patients with baseline HbA1c >= 6.5%

This population includes the FAS with baseline HbA1c >= 6.5%. Non-completers were considered as failure imputation (NCF).

Posted

Number

percentage of patients

Baseline and week 24

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

Percentage of Patients With HbA1c<6.5% at Week 24

This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).

Posted

Number

percentage of patients

Baseline and week 24

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24

The percentage of patients with an HbA1c reduction from baseline >= 0.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5%.

The Full Analysis Set (FAS) included all patients with a baseline and at least one on treatment HbA1c measurement available. Non-completers were considered as failure imputation (NCF).

Posted

Number

percentage of patients

Baseline and week 24

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

Adjusted Means for 2h Post Prandial Blood Glucose (PPG) Change From Baseline at Week 24

This change from baseline reflects the Week 24 2h PPG minus the baseline 2h PPG. Means are treatment adjusted for baseline HbA1c, baseline PPG and previous anti-diabetic medication.

Meal Tolerance Test (MTT) set (treated and randomised patients with adequate MTT results available at the beginning and end of the randomised treatment period)

Posted

Mean

Standard Error

mg/dL

Baseline and week 24

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Secondary

2 Hour Post-Prandial Glucose (PPG) Increment Over Fasting Plasma Glucose (FPG) at Week 24

This change from baseline reflects the Week 24 (2h PPG - FPG) minus the baseline (2h PPG - FPG). Means are treatment adjusted for baseline HbA1c, baseline 2h PPG increment over FPG and previous anti-diabetic medication.

Meal Tolerance Test (MTT) set (treated and randomised patients with adequate MTT results available at the beginning and end of the randomised treatment period)

Posted

Least Squares Mean

Standard Error

mg/dL

Baseline and week 24

ID	Title	Description
OG000	Placebo	Patients randomized to receive treatment with matching placebo
OG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Angina pectoris	Cardiac disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Atrial fibrillation	Cardiac disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Myocardial infarction	Cardiac disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Myocardial ischaemia	Cardiac disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Non-cardiac chest pain	General disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Blebitis	Infections and infestations	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Gastroenteritis	Infections and infestations	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Gastroenteritis viral	Infections and infestations	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Hepatitis viral	Infections and infestations	MedDRA 12.0	Systematic Assessment	EG0001 affected177 at risk EG0010 affected523 at risk
Avulsion fracture	Injury, poisoning and procedural complications	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Snake bite	Injury, poisoning and procedural complications	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Ulna fracture	Injury, poisoning and procedural complications	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Intervertebral disc protrusion	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected177 at risk EG0011 affected523 at risk
Cerebral ischaemia	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected177 at risk EG0010 affected523 at risk
Headache	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected177 at risk EG0010 affected523 at risk
Calculus ureteric	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0012 affected523 at risk
Nephrolithiasis	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0012 affected523 at risk
Renal mass	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Rectocele	Reproductive system and breast disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected177 at risk EG0010 affected523 at risk
Bronchial hyperreactivity	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk
Hypertension	Vascular disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected177 at risk EG0011 affected523 at risk

ID	Term
D003920	Diabetes Mellitus
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D004700	Endocrine System Diseases

ID	Term
D011687	Purines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D011799	Quinazolines

ID	Title	Description
BG000	Placebo	Patients randomized to receive treatment with matching placebo
BG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Patients randomized to receive treatment with matching placebo			4	177	34	177
EG001	Linagliptin	Patients randomized to receive treatment with Linagliptin 5 mg			18	523	54	523

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Nasopharyngitis	Infections and infestations	MedDRA 12.0	Systematic Assessment		EG0009 affected177 at risk EG00127 affected523 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 12.0	Systematic Assessment		EG00026 affected177 at risk EG00127 affected523 at risk