Diabetes Mellitus, Type 2
Conditions
Brief summary
Reduced factorial design study with 24 week randomized treatment of initial combination therapy with linagliptin and metformin in T2DM patients
Interventions
DRUGlinagliptin2.5mg/metformin1000mg
linagliptin2.5mg/metformin1000mg BID
DRUGlinagliptin 5mg
linagliptin 5mg once daily
DRUGMetformin 500mg
Metformin 500mg BID
DRUGlinagliptin2.5mg/metformin500mg
linagliptin2.5mg/metformin500mg BID
DRUGMetformin 1000mg
Metformin 1000mg BID
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Type 2 diabetes mellitus(T2DM) prior to informed consent 2. Male and female patients on diet and exercise regimen who are drug-naïve 3. Glycosylated haemoglobin A1c (HbA1c) at V1a \>/=7.5 %\<11% for main group and HbA1c \>/= 11.0 % for the additional parallel group 4. Age \>/= 18 and \</= 80 years at Visit 1a (Screening) 5. Body Mass Index(BMI)\</ = 40 kg/m2 at Visit 1a (Screening) 6. Signed and dated written informed consent by date of Visit 1a in accordance with good clinical practice(GCP) and local legislation
Exclusion criteria
1. Uncontrolled hyperglycaemia required for rescue medication during placebo run-in phase 2. In main group, the patients with investigational medicinal product(IMP) compliance \< 80 % or \>120 % during 2 weeks placebo run in period 3. Acute coronary syndrome stroke or Transient ischaemic attack (TIA) within 3 months prior to randomisation 4. Impaired hepatic function, defined by serum levels of either Alanine aminotransferase(ALT) ,Aspartate aminotransferase(AST), or alkaline phosphatase (AP) above 3 x upper limit of normal (ULN) ,or total bilirubin above 1.5 x ULN as determined at Visit 1a 5. Known hypersensitivity or allergy to linagliptin or its excipients or metformin or placebo 6. Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at the time of screening 7. 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 in the opinion of the investigator. 8. Concurrent participation in another clinical trial or any investigational therapy within thirty days prior to signing the consent form or during the trial. 9. 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 10. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent. 11. Renal failure or renal impairment at Visit 1a (screening) with an Estimated Glomerular Filtration Rate(eGFR) \< 60 ml/min 12. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption 13. Dehydration by clinical judgement of the investigator 14. Clinical detected unstable or acute congestive heart failure 15. Acute or chronic metabolic acidosis (present in patient history) 16. Hereditary galactose intolerance 17. Known history of pancreatitis and chronic pancreatitis 18. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within last 5 years. 19. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial at the discretion of investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group | Baseline and week 24 | The change from baseline in HbA1c after 24 weeks of treatment in main group. The mean was adjusted by baseline HbA1c and treatment group. |
| The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group - FAS (OC) | Baseline and week 24 | The change from baseline in HbA1c after 24 weeks of treatment in main group. Only subjects from the FAS with measured HbA1c values (observed cases \[OC\]) were considered. The mean was adjusted by treatment, baseline HbA1c, week and treatment\*week. The sensitivity analysis was added as the primary analysis failed with borderline results. |
| The Change From Baseline in HbA1c After 12 Weeks of Treatment in APG | Baseline and week 12 | The change from baseline in HbA1c after 12 weeks of treatment in additional parallel group (APG) The mean was adjusted by baseline HbA1c and treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 12 Weeks of Treatment in APG | Week 12 (after first drug administration) | The occurrence of treat to target efficacy response in terms of HbA1c \< 6.5% after 12 weeks of treatment in APG. |
| The Occurrence of Relative Efficacy Response in Main Group | From baseline until week 24 | The occurrence of relative efficacy response (HbA1c lowering by at least 0.5% after 24 weeks of treatment) in main group |
| The Occurrence of Relative Efficacy Response in APG | From baseline until week 12 | The Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 12 Weeks of Treatment) in APG |
| The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 24 Weeks of Treatment in Main Group | Week 24 (after first drug administration) | The occurrence of treat to target efficacy response in terms of HbA1c \< 7.0 % after 24 weeks of treatment in main group. |
| The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG | Baseline and week 12 | The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG. Adjusted mean: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group. |
| The Frequency of Patients With Use of Rescue Therapy During 24 Week Treatment Period in Main Group | From baseline until week 24 | The frequency of patients with use of rescue therapy during 24 week treatment period in main group. For this analysis the main group contrast 'Metformin 1000mg BID, Linagliptin 2.5mg / Metformin 1000mg BID' could not be analysed due to lack of events in the Metformin 1000mg BID group. |
| The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG | From baseline until week 12 | The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG. |
| The Change in Fasting Plasma Glucose (FPG) From Baseline After 24 Weeks of Treatment in Main Group | Baseline and week 24 | The change in fasting plasma glucose (FPG) from baseline after 24 weeks of treatment in main group. Adjusted mean: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group. |
| The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 12 Weeks of Treatment in APG | Week 12 (after first drug administration) | The occurrence of treat to target efficacy response in terms of HbA1c \< 7.0 % after 12 weeks of treatment in APG. |
| The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 24 Weeks of Treatment in Main Group | Week 24 (after first drug administration) | The occurrence of treat to target efficacy response in terms of HbA1c \< 6.5% after 24 weeks of treatment in main group. |
Countries
China, Malaysia, Philippines, Vietnam
Participant flow
Pre-assignment details
After 2-weeks placebo run-in in the main group, 730 of 733 randomised patients were treated in a double-blind fashion for 24 weeks. In the additional parallel group (APG), all of 143 randomised patients with HbA1c \>=11% were treated for 24 weeks (the first 12 weeks were double-blind). There was a 1-week follow-up period after treatment.
Participants by arm
| Arm | Count |
|---|---|
| Main: Linagliptin 5mg QD Main Group: Patients received linagliptin 5mg QD, administered oral as tablet. | 147 |
| Main: Metformin 500mg BID Main Group: Patients received metformin 500mg BID, administered oral as tablet. | 145 |
| Main: Metformin 1000mg BID Main Group: Patients received metformin 1000mg BID, administered oral as tablet. | 144 |
| Main: Linagliptin 2.5mg / Metformin 500mg BID Main Group: Patients received linagliptin 2.5mg and metformin 500mg BID, administered oral as fixed dose combination (FDC) tablet. | 147 |
| Main: Linagliptin 2.5mg / Metformin 1000mg BID Main Group: Patients received linagliptin 2.5mg and metformin 1000mg BID, administered oral as fixed dose combination (FDC) tablet. | 147 |
| APG: Linagliptin 5mg QD Additional parallel group (APG): Patients received linagliptin 5mg QD, administered oral as tablet.
(Data up to week 12) | 71 |
| APG: Linagliptin 2.5mg / Metformin 1000mg BID Additional parallel group (APG): Patients received linagliptin 2.5mg and metformin 1000mg BID, administered oral as fixed dose combination (FDC) tablet.
(Data up to week 12) | 72 |
| Total | 873 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 | 9 | 2 | 7 | 3 | 5 |
| Overall Study | Lack of Efficacy | 3 | 1 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 | 2 | 2 | 0 | 0 | 1 |
| Overall Study | Non compliance with protocol | 0 | 2 | 1 | 3 | 0 | 0 | 0 |
| Overall Study | Other Reason | 1 | 0 | 1 | 1 | 1 | 2 | 0 |
| Overall Study | Refused to continue trial medication | 8 | 0 | 4 | 2 | 8 | 1 | 1 |
Baseline characteristics
| Characteristic | Main: Linagliptin 5mg QD | Main: Metformin 500mg BID | Main: Metformin 1000mg BID | Main: Linagliptin 2.5mg / Metformin 500mg BID | Main: Linagliptin 2.5mg / Metformin 1000mg BID | APG: Linagliptin 5mg QD | APG: Linagliptin 2.5mg / Metformin 1000mg BID | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 50.8 years STANDARD_DEVIATION 10.5 | 52.1 years STANDARD_DEVIATION 9.6 | 51.4 years STANDARD_DEVIATION 10.4 | 51.4 years STANDARD_DEVIATION 10.2 | 50.7 years STANDARD_DEVIATION 9.4 | 49.5 years STANDARD_DEVIATION 11.6 | 49.9 years STANDARD_DEVIATION 11.7 | 51.0 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 71 Participants | 54 Participants | 53 Participants | 55 Participants | 60 Participants | 23 Participants | 32 Participants | 348 Participants |
| Sex: Female, Male Male | 76 Participants | 91 Participants | 91 Participants | 92 Participants | 87 Participants | 48 Participants | 40 Participants | 525 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 30 / 147 | 31 / 145 | 42 / 144 | 32 / 147 | 41 / 147 | 20 / 71 | 15 / 72 | 2 / 33 | 9 / 31 | 9 / 65 |
| serious Total, serious adverse events | 2 / 147 | 1 / 145 | 2 / 144 | 1 / 147 | 4 / 147 | 1 / 71 | 1 / 72 | 0 / 33 | 1 / 31 | 1 / 65 |
Outcome results
Primary
The Change From Baseline in HbA1c After 12 Weeks of Treatment in APG
The change from baseline in HbA1c after 12 weeks of treatment in additional parallel group (APG) The mean was adjusted by baseline HbA1c and treatment group.
Time frame: Baseline and week 12
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main: Linagliptin 5mg QD | The Change From Baseline in HbA1c After 12 Weeks of Treatment in APG | -3.46 percentage | Standard Error 0.22 |
| Main: Metformin 500mg BID | The Change From Baseline in HbA1c After 12 Weeks of Treatment in APG | -4.71 percentage | Standard Error 0.22 |
Comparison: The treatment effect of the 'APG: Linagliptin 2.5mg / Metformin 1000mg BID' was compared with 'APG: Linagliptin 5mg QD'.~The model includes treatment as a fixed effect and baseline HbA1c as a linear covariate.p-value: 0.000195% CI: [-1.87, -0.63]ANCOVA
Primary
The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group
The change from baseline in HbA1c after 24 weeks of treatment in main group. The mean was adjusted by baseline HbA1c and treatment group.
Time frame: Baseline and week 24
Population: Full analysis set (FAS): all randomised and treated patients who had a baseline and at least 1 on-treatment HbA1c value As the imputation rule for missing data the last observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main: Linagliptin 5mg QD | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group | -1.29 percentage | Standard Error 0.08 |
| Main: Metformin 500mg BID | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group | -1.64 percentage | Standard Error 0.08 |
| Main: Metformin 1000mg BID | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group | -2.07 percentage | Standard Error 0.08 |
| Main: Linagliptin 2.5mg / Metformin 500mg BID | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group | -2.15 percentage | Standard Error 0.08 |
| Main: Linagliptin 2.5mg / Metformin 1000mg BID | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group | -2.29 percentage | Standard Error 0.08 |
Comparison: The model includes treatment as a fixed effect and baseline HbA1c as a linear covariate.~The null and alternative hypotheses were tested in a hierarchical sequence. The next null hypothesis was tested in a confirmatory way only if all prior null-hypotheses were rejected. 'Greater effect' refers to a greater reduction in HbA1c.p-value: 0.058795% CI: [-0.45, 0.01]ANCOVA
Comparison: The model includes treatment as a fixed effect and baseline HbA1c as a linear covariate.~The null and alternative hypotheses were tested in a hierarchical sequence. The next null hypothesis was tested in a confirmatory way only if all prior null-hypotheses were rejected. 'Greater effect' refers to a greater reduction in HbA1c.p-value: <0.000195% CI: [-1.23, -0.78]ANCOVA
Comparison: The model includes treatment as a fixed effect and baseline HbA1c as a linear covariate.~The null and alternative hypotheses were tested in a hierarchical sequence. The next null hypothesis was tested in a confirmatory way only if all prior null-hypotheses were rejected. 'Greater effect' refers to a greater reduction in HbA1c.p-value: <0.000195% CI: [-0.73, -0.29]ANCOVA
Comparison: The model includes treatment as a fixed effect and baseline HbA1c as a linear covariate.~The null and alternative hypotheses were tested in a hierarchical sequence. The next null hypothesis was tested in a confirmatory way only if all prior null-hypotheses were rejected. 'Greater effect' refers to a greater reduction in HbA1c.p-value: <0.000195% CI: [-1.09, -0.64]ANCOVA
Primary
The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group - FAS (OC)
The change from baseline in HbA1c after 24 weeks of treatment in main group. Only subjects from the FAS with measured HbA1c values (observed cases \[OC\]) were considered. The mean was adjusted by treatment, baseline HbA1c, week and treatment\*week. The sensitivity analysis was added as the primary analysis failed with borderline results.
Time frame: Baseline and week 24
Population: FAS (OC): subjects from the FAS with measured HbA1c values (observed cases \[OC\]) were considered
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main: Linagliptin 5mg QD | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group - FAS (OC) | -1.34 percentage | Standard Error 0.08 |
| Main: Metformin 500mg BID | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group - FAS (OC) | -1.68 percentage | Standard Error 0.08 |
| Main: Metformin 1000mg BID | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group - FAS (OC) | -2.08 percentage | Standard Error 0.08 |
| Main: Linagliptin 2.5mg / Metformin 500mg BID | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group - FAS (OC) | -2.16 percentage | Standard Error 0.08 |
| Main: Linagliptin 2.5mg / Metformin 1000mg BID | The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group - FAS (OC) | -2.38 percentage | Standard Error 0.08 |
Comparison: Sensitivity analysis: Mixed Model for repeated measurements~The model includes baseline HbA1c as a linear covariate; visit, treatment and visit by treatment interaction as fixed classification effects and patient as a random effect with unstructured covariance structure to model within-patients errors.p-value: 0.010995% CI: [-0.53, -0.07]ANCOVA
Comparison: Sensitivity analysis: Mixed Model for repeated measurements~The model includes baseline HbA1c as a linear covariate; visit, treatment and visit by treatment interaction as fixed classification effects and patient as a random effect with unstructured covariance structure to model within-patients errors.p-value: <0.000195% CI: [-1.27, -0.81]ANCOVA
Comparison: Sensitivity analysis: Mixed Model for repeated measurements~The model includes baseline HbA1c as a linear covariate; visit, treatment and visit by treatment interaction as fixed classification effects and patient as a random effect with unstructured covariance structure to model within-patients errors.p-value: <0.000195% CI: [-0.7, -0.24]ANCOVA
Comparison: Sensitivity analysis: Mixed Model for repeated measurements~The model includes baseline HbA1c as a linear covariate; visit, treatment and visit by treatment interaction as fixed classification effects and patient as a random effect with unstructured covariance structure to model within-patients errors.p-value: <0.000195% CI: [-1.04, -0.58]ANCOVA
Secondary
The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG
The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG. Adjusted mean: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group.
Time frame: Baseline and week 12
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main: Linagliptin 5mg QD | The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG | -56.70 mg/dL | Standard Error 6.53 |
| Main: Metformin 500mg BID | The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG | -91.92 mg/dL | Standard Error 6.48 |
Comparison: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group.p-value: 0.000295% CI: [-53.48, -16.95]ANCOVA
Secondary
The Change in Fasting Plasma Glucose (FPG) From Baseline After 24 Weeks of Treatment in Main Group
The change in fasting plasma glucose (FPG) from baseline after 24 weeks of treatment in main group. Adjusted mean: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group.
Time frame: Baseline and week 24
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main: Linagliptin 5mg QD | The Change in Fasting Plasma Glucose (FPG) From Baseline After 24 Weeks of Treatment in Main Group | -15.03 mg/dL | Standard Error 2.25 |
| Main: Metformin 500mg BID | The Change in Fasting Plasma Glucose (FPG) From Baseline After 24 Weeks of Treatment in Main Group | -29.87 mg/dL | Standard Error 2.23 |
| Main: Metformin 1000mg BID | The Change in Fasting Plasma Glucose (FPG) From Baseline After 24 Weeks of Treatment in Main Group | -42.07 mg/dL | Standard Error 2.31 |
| Main: Linagliptin 2.5mg / Metformin 500mg BID | The Change in Fasting Plasma Glucose (FPG) From Baseline After 24 Weeks of Treatment in Main Group | -39.33 mg/dL | Standard Error 2.24 |
| Main: Linagliptin 2.5mg / Metformin 1000mg BID | The Change in Fasting Plasma Glucose (FPG) From Baseline After 24 Weeks of Treatment in Main Group | -47.44 mg/dL | Standard Error 2.26 |
Comparison: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group.p-value: 0.097195% CI: [-11.72, 0.98]ANCOVA
Comparison: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group.p-value: <0.000195% CI: [-38.67, -26.16]ANCOVA
Comparison: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group.p-value: 0.002895% CI: [-15.66, -3.27]ANCOVA
Comparison: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group.p-value: <0.000195% CI: [-30.54, -18.08]ANCOVA
Secondary
The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG
The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG.
Time frame: From baseline until week 12
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main: Linagliptin 5mg QD | The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG | 10.0 percentage of participants |
| Main: Metformin 500mg BID | The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG | 1.5 percentage of participants |
Comparison: Comparison of 'APG: Linagliptin 2.5mg / Metformin 1000mg BID' / 'APG: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.047495% CI: [0.013, 0.976]Regression, Logistic
Secondary
The Frequency of Patients With Use of Rescue Therapy During 24 Week Treatment Period in Main Group
The frequency of patients with use of rescue therapy during 24 week treatment period in main group. For this analysis the main group contrast 'Metformin 1000mg BID, Linagliptin 2.5mg / Metformin 1000mg BID' could not be analysed due to lack of events in the Metformin 1000mg BID group.
Time frame: From baseline until week 24
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main: Linagliptin 5mg QD | The Frequency of Patients With Use of Rescue Therapy During 24 Week Treatment Period in Main Group | 7.1 percentage of participants |
| Main: Metformin 500mg BID | The Frequency of Patients With Use of Rescue Therapy During 24 Week Treatment Period in Main Group | 2.1 percentage of participants |
| Main: Metformin 1000mg BID | The Frequency of Patients With Use of Rescue Therapy During 24 Week Treatment Period in Main Group | 0.0 percentage of participants |
| Main: Linagliptin 2.5mg / Metformin 500mg BID | The Frequency of Patients With Use of Rescue Therapy During 24 Week Treatment Period in Main Group | 1.4 percentage of participants |
| Main: Linagliptin 2.5mg / Metformin 1000mg BID | The Frequency of Patients With Use of Rescue Therapy During 24 Week Treatment Period in Main Group | 2.1 percentage of participants |
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 1000mg BID' / 'Main: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c. The validity of the model is questionable as there is possibly a quasi-complete separation of data points, the results shown are based on the last maximum likelihood iteration.p-value: 0.027195% CI: [0.052, 0.838]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 500mg BID' / 'Main: Metformin 500mg BID'.~The logistic regression includes treatment and continuous baseline HbA1c. The validity of the model is questionable as there is possibly a quasi-complete separation of data points, the results shown are based on the last maximum likelihood iteration.p-value: 0.969995% CI: [0.15, 6.202]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 500mg BID' / 'Main: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c. The validity of the model is questionable as there is possibly a quasi-complete separation of data points, the results shown are based on the last maximum likelihood iteration.p-value: 0.034395% CI: [0.038, 0.882]Regression, Logistic
Secondary
The Occurrence of Relative Efficacy Response in APG
The Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 12 Weeks of Treatment) in APG
Time frame: From baseline until week 12
Population: FAS (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main: Linagliptin 5mg QD | The Occurrence of Relative Efficacy Response in APG | 84.3 percentage of participants |
| Main: Metformin 500mg BID | The Occurrence of Relative Efficacy Response in APG | 91.2 percentage of participants |
Comparison: Comparison of 'APG: Linagliptin 2.5mg / Metformin 1000mg BID' / 'APG: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.252395% CI: [0.642, 5.42]Regression, Logistic
Secondary
The Occurrence of Relative Efficacy Response in Main Group
The occurrence of relative efficacy response (HbA1c lowering by at least 0.5% after 24 weeks of treatment) in main group
Time frame: From baseline until week 24
Population: FAS (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main: Linagliptin 5mg QD | The Occurrence of Relative Efficacy Response in Main Group | 73.0 percentage of participants |
| Main: Metformin 500mg BID | The Occurrence of Relative Efficacy Response in Main Group | 80.6 percentage of participants |
| Main: Metformin 1000mg BID | The Occurrence of Relative Efficacy Response in Main Group | 89.5 percentage of participants |
| Main: Linagliptin 2.5mg / Metformin 500mg BID | The Occurrence of Relative Efficacy Response in Main Group | 93.0 percentage of participants |
| Main: Linagliptin 2.5mg / Metformin 1000mg BID | The Occurrence of Relative Efficacy Response in Main Group | 89.4 percentage of participants |
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 1000mg BID' / 'Main: Metformin 1000mg BID'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.970595% CI: [0.456, 2.13]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 1000mg BID' / 'Main: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.000795% CI: [1.612, 5.938]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 500mg BID' / 'Main: Metformin 500mg BID'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.002995% CI: [1.486, 6.849]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 500mg BID' / 'Main: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: <0.000195% CI: [2.318, 10.238]Regression, Logistic
Secondary
The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 12 Weeks of Treatment in APG
The occurrence of treat to target efficacy response in terms of HbA1c \< 6.5% after 12 weeks of treatment in APG.
Time frame: Week 12 (after first drug administration)
Population: FAS (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main: Linagliptin 5mg QD | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 12 Weeks of Treatment in APG | 15.7 percentage of participants |
| Main: Metformin 500mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 12 Weeks of Treatment in APG | 36.8 percentage of participants |
Comparison: Comparison of 'APG: Linagliptin 2.5mg / Metformin 1000mg BID' / 'APG: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.006295% CI: [1.383, 7.11]Regression, Logistic
Secondary
The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 24 Weeks of Treatment in Main Group
The occurrence of treat to target efficacy response in terms of HbA1c \< 6.5% after 24 weeks of treatment in main group.
Time frame: Week 24 (after first drug administration)
Population: FAS (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main: Linagliptin 5mg QD | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 24 Weeks of Treatment in Main Group | 23.4 percentage of participants |
| Main: Metformin 500mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 24 Weeks of Treatment in Main Group | 34.7 percentage of participants |
| Main: Metformin 1000mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 24 Weeks of Treatment in Main Group | 50.4 percentage of participants |
| Main: Linagliptin 2.5mg / Metformin 500mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 24 Weeks of Treatment in Main Group | 56.3 percentage of participants |
| Main: Linagliptin 2.5mg / Metformin 1000mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 24 Weeks of Treatment in Main Group | 60.3 percentage of participants |
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 1000mg BID' / 'Main: Metformin 1000mg BID'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.04895% CI: [1.004, 2.746]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 1000mg BID' / 'Main: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: <0.000195% CI: [3.452, 10.164]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 500mg BID' / 'Main: Metformin 500mg BID'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.000295% CI: [1.563, 4.239]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 500mg BID' / 'Main: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: <0.000195% CI: [2.751, 7.968]Regression, Logistic
Secondary
The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 12 Weeks of Treatment in APG
The occurrence of treat to target efficacy response in terms of HbA1c \< 7.0 % after 12 weeks of treatment in APG.
Time frame: Week 12 (after first drug administration)
Population: FAS (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main: Linagliptin 5mg QD | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 12 Weeks of Treatment in APG | 27.1 percentage of participants |
| Main: Metformin 500mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 12 Weeks of Treatment in APG | 58.8 percentage of participants |
Comparison: Comparison of 'APG: Linagliptin 2.5mg / Metformin 1000mg BID' / 'APG: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.000195% CI: [1.997, 8.701]Regression, Logistic
Secondary
The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 24 Weeks of Treatment in Main Group
The occurrence of treat to target efficacy response in terms of HbA1c \< 7.0 % after 24 weeks of treatment in main group.
Time frame: Week 24 (after first drug administration)
Population: FAS - non-completers were considered as nonresponders (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Main: Linagliptin 5mg QD | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 24 Weeks of Treatment in Main Group | 43.6 percentage of participants |
| Main: Metformin 500mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 24 Weeks of Treatment in Main Group | 50.0 percentage of participants |
| Main: Metformin 1000mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 24 Weeks of Treatment in Main Group | 69.0 percentage of participants |
| Main: Linagliptin 2.5mg / Metformin 500mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 24 Weeks of Treatment in Main Group | 72.1 percentage of participants |
| Main: Linagliptin 2.5mg / Metformin 1000mg BID | The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 24 Weeks of Treatment in Main Group | 77.1 percentage of participants |
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 1000mg BID' / 'Main: Metformin 1000mg BID'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: 0.077195% CI: [0.946, 2.961]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 1000mg BID' / 'Main: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: <0.000195% CI: [3.164, 9.522]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 500mg BID' / 'Main: Metformin 500mg BID'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: <0.000195% CI: [1.678, 4.767]Regression, Logistic
Comparison: Comparison of 'Main: Linagliptin 2.5mg / Metformin 500mg BID' / 'Main: Linagliptin 5mg QD'.~The logistic regression includes treatment and continuous baseline HbA1c.p-value: <0.000195% CI: [2.259, 6.454]Regression, Logistic