Diabetes Mellitus, Type 2
Conditions
Brief summary
In this randomised, double-blind, parallel group trial, the safety and efficacy of 5 mg of Linagliptin administered orally once daily will be compared with a placebo after 24 weeks of treatment as add-on therapy to metformin in patients with type 2 diabetes and insufficient glycaemic control.
Interventions
DRUGLinagliptin
once a day
DRUGplacebo
once a day
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. 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 (antidiabetic therapy has to be unchanged for 6 weeks prior to informed consent and patients should receive standard diet and exercise counseling) A dose of \>/=1500 mg/day metformin is required for inclusion into the trial. The dosage needs to be stable for at least 8 weeks before randomisation. Patients with a total daily dose of less than 1500 mg metformin will only be included; if the investigator has documented them to be on their maximum tolerated dose (also in this case the 8 week time interval will apply for a stable dose). 2. Diagnosis of type 2 diabetes prior to informed consent 3. Glycosylated haemoglobin A1 (HbA1c) at Visit 1a (Screening): For patients undergoing wash out of previous medication: HbA1c =7.0 to =9.5% For patients not undergoing wash-out of previous medication: HbA1c =7.0 to =10.0% 4. Glycosylated haemoglobin A1 (HbA1c) =7.0 to =10.0% at Visit 2 (Start of Run-in) 5. Age = 18 and \< 80 years at Visit 1a (Screening) 6. BMI (Body Mass Index) = 45 kg/m2 at Visit 1a (Screening) 7. Signed and dated written informed consent by date of Visit 1a in accordance with GCP and local legislation
Exclusion criteria
1. Myocardial infarction, stroke or TIA within 6 months prior to informed consent 2. Impaired hepatic function, defined by serum levels of either Alanine transaminase,Aspartate transaminase, or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at Visit 1a 3. Uncontrolled hyperglycaemia with a glucose level \>240 mg/dl (\>13.3 mmol/L) after an overnight fast during wash-out / placebo run-in and confirmed by a second measurement (not on the same day). 4. Known hypersensitivity or allergy to the investigational product or its excipients or metformin or placebo 5. Treatment with rosiglitazone or pioglitazone within 3 months prior to informed consent 6. Treatment with an injectable Glucagon-like peptide- 1 (GLP-1) analogue (e.g. exenatide) , Dipeptidyl-Peptidase 4 (DPP-IV) inhibitor within 3 months prior to informed consent 7. Treatment with insulin within 3 months prior to informed consent 8. Treatment with anti-obesity drugs (e.g. sibutramine, orlistat, rimonabant) within 3 months prior to informed consent. 9. Alcohol abuse within the 3 months prior to informed consent that would interfere with trial participation or drug abuse 10. Participation in another trial with an investigational drug within 2 months prior to informed consent 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 transdermal patch, intra-uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence and vasectomised partner. No exception will be made. 12. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent. 13. Renal failure or renal impairment (serum creatinine =1.5 mg/dl as determined at Visit 1a) 14. Dehydration by clinical judgement of the investigator 15. Unstable or acute congestive heart failure 16. Acute or chronic metabolic acidosis (present in patient history) 17. Hereditary galactose intolerance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline at Week 24 | Baseline and at week 24 | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With HbA1c < 7.0% at Week 24 With Baseline HbA1c >= 7.0%. | baseline and at week 24 | Number of patients with HbA1c \< 7.0% at week 24 with baseline HbA1c \>= 7.0%. |
| Number of Patients With HbA1c < 6.5% | baseline and at week 24 | Number of patients with HbA1c \< 6.5% at week 24 |
| FPG Change From Baseline at Week 18 | Baseline and at week 18 | Means are treatment adjusted for baseline FPG and previous anti-diabetic medication. |
| HbA1c Change From Baseline at Week 6 | Baseline and at week 6 | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
| HbA1c Change From Baseline at Week 12 | Baseline and at week 12 | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
| HbA1c Change From Baseline at Week 18 | Baseline and at week 18 | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
| Number of Patients With HbA1c < 7.0% | baseline and at week 24 | Number of patients with HbA1c \< 7.0% at week 24 |
| FPG Change From Baseline at Week 24 | Baseline and at week 24 | Means are treatment adjusted for baseline fasting plasma glucose (FPG) and previous anti-diabetic medication. |
| FPG Change From Baseline at Week 6 | Baseline and at week 6 | Means are treatment adjusted for baseline FPG and previous anti-diabetic medication. |
| FPG Change From Baseline at Week 12 | Baseline and at week 12 | Means are treatment adjusted for baseline FPG and previous anti-diabetic medication. |
| Number of Patients With HbA1c < 6.5% at Week 24 With Baseline HbA1c >= 6.5%. | baseline and at week 24 | Number of patients with HbA1c \< 6.5% at week 24 with baseline HbA1c \>= 6.5%. |
| Number With HbA1c at Least Lowering 0.5% | baseline and at week 24 | Number with HbA1c at least 0.5% lowering from baseline at week 24 |
| HbA1c Change From Baseline at Week 24(Chinese Only) | Baseline and at 24 weeks | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
Countries
China, Malaysia, Philippines
Participant flow
Recruitment details
A total of 614 patients were screened in 19 centres in China, Malaysia,and Philippines.A total of 306 patients were randomised in a 1:2 ratio to receive either placebo (101 patients) or linagliptin 5 mg (205 patients) in addition to metformin.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo | 100 |
| Linagliptin 5mg Linagliptin 5mg, once daily tablets, oral | 205 |
| Total | 305 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Lack of Efficacy | 0 | 3 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | patient's private reason | 1 | 1 |
| Overall Study | patient's refusal to come | 2 | 2 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 3 |
Baseline characteristics
| Characteristic | Placebo | Linagliptin 5mg | Total |
|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 8.7 | 55.1 years STANDARD_DEVIATION 10.7 | 55.5 years STANDARD_DEVIATION 10.1 |
| Baseline fasting plasma glucose | 157.7 mg/dL STANDARD_DEVIATION 36.8 | 160.5 mg/dL STANDARD_DEVIATION 40.1 | 159.6 mg/dL STANDARD_DEVIATION 39 |
| Baseline HbA1c | 8.00 % STANDARD_DEVIATION 0.8 | 7.99 % STANDARD_DEVIATION 0.83 | 7.99 % STANDARD_DEVIATION 0.82 |
| BMI | 25.8 kg/m^2 STANDARD_DEVIATION 4 | 25.5 kg/m^2 STANDARD_DEVIATION 3.9 | 25.6 kg/m^2 STANDARD_DEVIATION 4 |
| Sex: Female, Male Female | 50 Participants | 103 Participants | 153 Participants |
| Sex: Female, Male Male | 50 Participants | 102 Participants | 152 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 100 | 29 / 205 |
| serious Total, serious adverse events | 2 / 100 | 4 / 205 |
Outcome results
Primary
HbA1c Change From Baseline at Week 24
Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and at week 24
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 24 | -0.14 Percent | Standard Error 0.07 |
| Linagliptin 5mg | HbA1c Change From Baseline at Week 24 | -0.66 Percent | Standard Error 0.05 |
p-value: <0.000195% CI: [-0.7, -0.34]ANCOVA
Secondary
FPG Change From Baseline at Week 12
Means are treatment adjusted for baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and at week 12
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline at Week 12 | -4.5 mg/dL | Standard Error 3 |
| Linagliptin 5mg | FPG Change From Baseline at Week 12 | -14.7 mg/dL | Standard Error 2.1 |
p-value: 0.00595% CI: [-17.3, -3.1]ANCOVA
Secondary
FPG Change From Baseline at Week 18
Means are treatment adjusted for baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and at week 18
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline at Week 18 | -1.9 mg/dL | Standard Error 3.4 |
| Linagliptin 5mg | FPG Change From Baseline at Week 18 | -13.4 mg/dL | Standard Error 2.4 |
p-value: 0.004495% CI: [-19.5, -3.6]ANCOVA
Secondary
FPG Change From Baseline at Week 24
Means are treatment adjusted for baseline fasting plasma glucose (FPG) and previous anti-diabetic medication.
Time frame: Baseline and at week 24
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline at Week 24 | -1.1 mg/dL | Standard Error 3.5 |
| Linagliptin 5mg | FPG Change From Baseline at Week 24 | -10.7 mg/dL | Standard Error 2.5 |
p-value: 0.023395% CI: [-17.8, -1.3]ANCOVA
Secondary
FPG Change From Baseline at Week 6
Means are treatment adjusted for baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and at week 6
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline at Week 6 | 5.3 mg/dL | Standard Error 2.8 |
| Linagliptin 5mg | FPG Change From Baseline at Week 6 | -16.8 mg/dL | Standard Error 2 |
p-value: <0.000195% CI: [-28.7, -15.6]ANCOVA
Secondary
HbA1c Change From Baseline at Week 12
Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and at week 12
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 12 | -0.062 Percent | Standard Error 0.068 |
| Linagliptin 5mg | HbA1c Change From Baseline at Week 12 | -0.653 Percent | Standard Error 0.048 |
p-value: <0.000195% CI: [-0.752, -0.43]ANCOVA
Secondary
HbA1c Change From Baseline at Week 18
Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and at week 18
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 18 | -0.119 Percent | Standard Error 0.073 |
| Linagliptin 5mg | HbA1c Change From Baseline at Week 18 | -0.645 Percent | Standard Error 0.052 |
p-value: <0.000195% CI: [-0.7, -0.35]ANCOVA
Secondary
HbA1c Change From Baseline at Week 24(Chinese Only)
Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and at 24 weeks
Population: The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available (Chinese only). Last observation carried forward (LOCF) was used as the imputation rule.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 24(Chinese Only) | -0.16 Percent | Standard Error 0.08 |
| Linagliptin 5mg | HbA1c Change From Baseline at Week 24(Chinese Only) | -0.68 Percent | Standard Error 0.06 |
p-value: <0.000195% CI: [-0.71, -0.32]ANCOVA
Secondary
HbA1c Change From Baseline at Week 6
Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and at week 6
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 6 | -0.02 Percent | Standard Error 0.052 |
| Linagliptin 5mg | HbA1c Change From Baseline at Week 6 | -0.455 Percent | Standard Error 0.037 |
p-value: <0.000195% CI: [-0.555, -0.311]ANCOVA
Secondary
Number of Patients With HbA1c < 6.5%
Number of patients with HbA1c \< 6.5% at week 24
Time frame: baseline and at week 24
Population: The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Patients With HbA1c < 6.5% | 4 Participants |
| Linagliptin 5mg | Number of Patients With HbA1c < 6.5% | 26 Participants |
Secondary
Number of Patients With HbA1c < 6.5% at Week 24 With Baseline HbA1c >= 6.5%.
Number of patients with HbA1c \< 6.5% at week 24 with baseline HbA1c \>= 6.5%.
Time frame: baseline and at week 24
Population: This population includes the FAS with baseline HbA1c \>= 6.5%. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Patients With HbA1c < 6.5% at Week 24 With Baseline HbA1c >= 6.5%. | 3 Participants |
| Linagliptin 5mg | Number of Patients With HbA1c < 6.5% at Week 24 With Baseline HbA1c >= 6.5%. | 26 Participants |
Comparison: Comparison by odds ratio for the patients with a baseline HbA1c \>= 6.5%p-value: 0.012995% CI: [1.404, 17.592]Regression, Logistic
Secondary
Number of Patients With HbA1c < 7.0%
Number of patients with HbA1c \< 7.0% at week 24
Time frame: baseline and at week 24
Population: The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Patients With HbA1c < 7.0% | 14 Participants |
| Linagliptin 5mg | Number of Patients With HbA1c < 7.0% | 82 Participants |
Secondary
Number of Patients With HbA1c < 7.0% at Week 24 With Baseline HbA1c >= 7.0%.
Number of patients with HbA1c \< 7.0% at week 24 with baseline HbA1c \>= 7.0%.
Time frame: baseline and at week 24
Population: This population includes the FAS with baseline HbA1c \>= 7.0%. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Patients With HbA1c < 7.0% at Week 24 With Baseline HbA1c >= 7.0%. | 9 Participants |
| Linagliptin 5mg | Number of Patients With HbA1c < 7.0% at Week 24 With Baseline HbA1c >= 7.0%. | 69 Participants |
Comparison: Comparison by odds ratio for the patients with a baseline HbA1c \>=7.0%p-value: <0.000195% CI: [2.831, 13.769]Regression, Logistic
Secondary
Number With HbA1c at Least Lowering 0.5%
Number with HbA1c at least 0.5% lowering from baseline at week 24
Time frame: baseline and at week 24
Population: The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number With HbA1c at Least Lowering 0.5% | 33 Participants |
| Linagliptin 5mg | Number With HbA1c at Least Lowering 0.5% | 120 Participants |
Comparison: Comparison by odds ratio for the patients with HbA1c at least lowering 0.5% from baselinep-value: <0.000195% CI: [1.799, 5.185]Regression, Logistic