Diabetes Mellitus, Type 2
Conditions
Brief summary
To evaluate the efficacy and safety of linagliptin compared to placebo when added on to insulin therapy alone or in combination with metformin in Chinese patients with type 2 diabetes mellitus with insufficient glycaemic control
Interventions
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of type 2 diabetes mellitus prior to informed consent. * Chinese male or female patients who are pre-treated with insulin alone or in combination with metformin: * With maximum insulin dose of \<= 1 unit/kg/day. Acceptable basal insulins could be insulin glargin, insulin detemir or NPH (neutral protamin hagedorn) insulin with duration of action up to 24 h; acceptable pre-mixed insulins could be preparations with 25/75 or 30/70 ratio, with once or twice daily posology only. The total insulin dose should not be changed by more than 10% of the baseline value within the 12 weeks prior to randomisation (Visit 3). Both human insulin & insulin analogue are accepted. * If the patient is taking metformin, stable dose (at least 1500 mg daily) must be maintained for at least 12 weeks without dose adjustments prior to randomisation (Visit 3). * HbA1c fulfills the following criteria: \>= 7.5 % to \<= 10.0 % at Visit 1. * Age \>= 18 years at Visit 1. * BMI \<= 45 kg/m2 (Body Mass Index) at Visit 1. * Women of childbearing potential must be ready and able to use highly effective methods of birth control per ICH (International Conference on Harmonisation) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. * A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. * Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. * Signed and dated written informed consent by date of Visit 1 in accordance with ICH-GCP (Good Clinical Practice) and local legislation
Exclusion criteria
* Uncontrolled hyperglycaemic with a glucose level \>240 mg/dl (\>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day). * Any other antidiabetic drug within 3 months prior to informed consent except those defined as background treatment via inclusion criterion 2. * Acute coronary syndrome (non-STEMI (ST Segment Elevation Myocardial Infarction), STEMI and unstable angina pectoris), stroke or TIA (Transient ischemic attack) within 3 months prior to informed consent. * Indication of liver disease, defined by serum levels of either ALT (Alanine aminotransferase) (SGPT (serum glutamic pyruvate transaminase )), AST (Aspartate aminotransferase) (SGOT (serum glutamic-oxaloacetic transaminase)), or alkaline phosphatase above 3 × upper limit of normal (ULN (upper limit of normal)) as determined during screening and/or run-in phase. * Any contraindications to metformin according to the local label for those patients that enter the study with metformin therapy as provided in ISF (Investigator Site File). * Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption. * Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years. * Blood dyscrasias or any disorders causing hemolysis or unstable Red Blood Cell (e.g. malaria, babesiosis, haemolytic anemia). * Known hypersensitivity or allergy to the investigational product or its recipients. * Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight. * Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T2DM (Type 2 diabetes mellitus). * Women who are pregnant, nursing, or who plan to become pregnant while in the trial. * 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. * Participation in another trial with an investigational drug within 2 months prior to informed consent or previous enrolment in this trial. * Any other clinical condition that would jeopardize patient's safety while participating in this clinical trial in the opinion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) After 24 Weeks of Treatment | Baseline and week 24 | Percentage change from baseline, that is, \[\[(HbA1c after 24 weeks of treatment) - (HbA1c at baseline)\] / (HbA1c at baseline)\] \*100%, where baseline refers to the last observation prior to the start of randomised study drug, including the observation prior to the placebo run-in. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour (2-h) Postprandial Plasma Glucose (PPG) After 24 Weeks of Treatment | Baseline and week 24 | Change from baseline in 2-hour (2-h) postprandial plasma glucose (PPG) after 24 weeks of treatment. |
| Percentage of Participants With HbA1c on Treatment <7.0 Percentage (%) After 24 Weeks of Treatment | 24 weeks | Percentage of participants with HbA1c on treatment \<7.0 percentage (%) after 24 weeks of treatment. Participants with baseline HbA1c \<7.0% were excluded from the analysis. |
| Percentage of Participants With HbA1c on Treatment < 6.5% After 24 Weeks of Treatment | 24 weeks | Percentage of participants with HbA1c on treatment \< 6.5% after 24 weeks of treatment. Participants with baseline HbA1c \<6.5% were excluded from the analysis. |
| Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks of Treatment | Baseline and week 24 | Change from baseline in Fasting plasma glucose (FPG) after 24 weeks of treatment. |
| Percentage of Participants With Any Investigator-defined Hypoglycaemic Adverse Event (AE) With Plasma Glucose (PG) ≤70 mg/dL | 24 weeks | Incidence of investigator-reported hypoglycaemic events confirmed by a measured blood glucose ≤70 mg/dL (≤3.9 Millimoles Per Litre (mmol/L)). Severe hypoglycaemic AE = hypoglycaemic event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. |
| Percentage of Participants With Any Severe Hypoglycaemic AE | 24 weeks | Incidence of severe hypoglycaemic events (requiring active assistance by another person, or fatal). Severe hypoglycaemic AE = hypoglycaemic event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. |
| Percentage of Participants With HbA1c Lowering by at Least 0.5% After 24 Weeks of Treatment | 24 weeks | Percentage of participants with HbA1c lowering by at least 0.5% after 24 weeks of treatment. |
Countries
China
Participant flow
Recruitment details
This was a randomised, double-blind, multi-centre, and placebo-controlled, parallel group study to compare linagliptin with placebo as add-on therapy to stable insulin alone (basal insulin, premixed insulin) or in combination with metformin in Chinese type 2 diabetes mellitus (T2DM) participants with insufficient glycaemic control.
Pre-assignment details
All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that all participants met all inclusion/exclusion criteria. Participants were not to be randomized to trial treatment if any one of the specific entry criteria were not met.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Linagliptin Participants were administered placebo matching 5 milligram (mg) linagliptin tablet once daily per os (p.o.) for 24 weeks. | 102 |
| Linagliptin Participants were administered 5 milligram (mg) linagliptin tablet once daily per os (p.o.) for 24 weeks. | 104 |
| Total | 206 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Other than listed above | 0 | 1 |
Baseline characteristics
| Characteristic | Linagliptin | Total | Placebo Matching Linagliptin |
|---|---|---|---|
| Age, Continuous | 60.1 Years STANDARD_DEVIATION 9.5 | 58.7 Years STANDARD_DEVIATION 10.2 | 57.1 Years STANDARD_DEVIATION 10.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 104 Participants | 206 Participants | 102 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 104 Participants | 206 Participants | 102 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 52 Participants | 100 Participants | 48 Participants |
| Sex: Female, Male Male | 52 Participants | 106 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 102 | 0 / 104 |
| other Total, other adverse events | 26 / 102 | 33 / 104 |
| serious Total, serious adverse events | 17 / 102 | 10 / 104 |
Outcome results
Primary
Percentage Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) After 24 Weeks of Treatment
Percentage change from baseline, that is, \[\[(HbA1c after 24 weeks of treatment) - (HbA1c at baseline)\] / (HbA1c at baseline)\] \*100%, where baseline refers to the last observation prior to the start of randomised study drug, including the observation prior to the placebo run-in.
Time frame: Baseline and week 24
Population: Full analysis set (FAS) observed cases (OC): The FAS consisted of all patients randomised in the TS who had a baseline HbA1c value and at least one on-treatment HbA1c value. The FAS was the basis for the intention-to-treat (ITT) analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Linagliptin | Percentage Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) After 24 Weeks of Treatment | -0.20 Percentage change | Standard Error 0.09 |
| Linagliptin | Percentage Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) After 24 Weeks of Treatment | -0.61 Percentage change | Standard Error 0.09 |
Comparison: Based on Mixed-effect Model Repeated Measures (MMRM) including fixed effects treatment, week, type of insulin, and treatment by week interaction, linear covariates baseline HbA1c, baseline HbA1c by week interaction and random effect for patient. Within-patient errors are modelled by unstructured covariance matrix. Adjusted mean is based on all patients in the model (not only patients with a baseline and week 24 measurement).p-value: 0.001695% CI: [-0.65, -0.16]Mixed model repeated measures
Secondary
Change From Baseline in 2-hour (2-h) Postprandial Plasma Glucose (PPG) After 24 Weeks of Treatment
Change from baseline in 2-hour (2-h) postprandial plasma glucose (PPG) after 24 weeks of treatment.
Time frame: Baseline and week 24
Population: Meal tolerance test (MTT) (OC) set: MTT-set consisted all patients of the FAS with a valid MTT at baseline and at the end of the study. An MTT was considered valid if it had a valid FPG and a valid 2-h PPG value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Linagliptin | Change From Baseline in 2-hour (2-h) Postprandial Plasma Glucose (PPG) After 24 Weeks of Treatment | -0.06 mg/dL | Standard Error 5.98 |
| Linagliptin | Change From Baseline in 2-hour (2-h) Postprandial Plasma Glucose (PPG) After 24 Weeks of Treatment | -32.01 mg/dL | Standard Error 5.66 |
Comparison: Based on analysis of covariance (ANCOVA) model including fixed effect treatment and type of insulin, and linear covariates baseline HbA1c and baseline 2-h PPG.p-value: 0.000195% CI: [-48.15, -15.75]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks of Treatment
Change from baseline in Fasting plasma glucose (FPG) after 24 weeks of treatment.
Time frame: Baseline and week 24
Population: FAS (OC)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Linagliptin | Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks of Treatment | 0.7 Milligram/Decilitre (mg/dL) | Standard Error 3.6 |
| Linagliptin | Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks of Treatment | -5.5 Milligram/Decilitre (mg/dL) | Standard Error 3.6 |
Comparison: Based on MMRM including fixed effects treatment, week, type of insulin, and treatment by week interaction, linear covariates baseline HbA1c, baseline FPG baseline FPG by week interaction and random effect for patient. Within-patient errors are modelled by unstructured covariance matrix. Adjusted mean is based on all patients in the model (not only patients with a baseline and week 24 measurement).p-value: 0.224195% CI: [-16.2, 3.8]Mixed model repeated measures
Secondary
Percentage of Participants With Any Investigator-defined Hypoglycaemic Adverse Event (AE) With Plasma Glucose (PG) ≤70 mg/dL
Incidence of investigator-reported hypoglycaemic events confirmed by a measured blood glucose ≤70 mg/dL (≤3.9 Millimoles Per Litre (mmol/L)). Severe hypoglycaemic AE = hypoglycaemic event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions.
Time frame: 24 weeks
Population: Treated set (TS) : The TS consisted of all patients treated with at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Matching Linagliptin | Percentage of Participants With Any Investigator-defined Hypoglycaemic Adverse Event (AE) With Plasma Glucose (PG) ≤70 mg/dL | 7.8 Percentage of Participants |
| Linagliptin | Percentage of Participants With Any Investigator-defined Hypoglycaemic Adverse Event (AE) With Plasma Glucose (PG) ≤70 mg/dL | 10.6 Percentage of Participants |
Secondary
Percentage of Participants With Any Severe Hypoglycaemic AE
Incidence of severe hypoglycaemic events (requiring active assistance by another person, or fatal). Severe hypoglycaemic AE = hypoglycaemic event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions.
Time frame: 24 weeks
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Matching Linagliptin | Percentage of Participants With Any Severe Hypoglycaemic AE | 0.0 Percentage of Participants |
| Linagliptin | Percentage of Participants With Any Severe Hypoglycaemic AE | 0.0 Percentage of Participants |
Secondary
Percentage of Participants With HbA1c Lowering by at Least 0.5% After 24 Weeks of Treatment
Percentage of participants with HbA1c lowering by at least 0.5% after 24 weeks of treatment.
Time frame: 24 weeks
Population: FAS (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Matching Linagliptin | Percentage of Participants With HbA1c Lowering by at Least 0.5% After 24 Weeks of Treatment | 36.0 Percentage of participants |
| Linagliptin | Percentage of Participants With HbA1c Lowering by at Least 0.5% After 24 Weeks of Treatment | 55.4 Percentage of participants |
Comparison: Logistic regression model with terms for treatment and type of insulin as fixed effect and continuous linear covariates baseline HbA1cp-value: 0.004995% CI: [1.286, 4.091]Regression, Logistic
Secondary
Percentage of Participants With HbA1c on Treatment < 6.5% After 24 Weeks of Treatment
Percentage of participants with HbA1c on treatment \< 6.5% after 24 weeks of treatment. Participants with baseline HbA1c \<6.5% were excluded from the analysis.
Time frame: 24 weeks
Population: FAS (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Matching Linagliptin | Percentage of Participants With HbA1c on Treatment < 6.5% After 24 Weeks of Treatment | 3.0 Percentage of participants |
| Linagliptin | Percentage of Participants With HbA1c on Treatment < 6.5% After 24 Weeks of Treatment | 4.0 Percentage of participants |
Comparison: Logistic regression model with terms for treatment and type of insulin as fixed effect and continuous linear covariates baseline HbA1cp-value: 0.623595% CI: [0.309, 7.105]Regression, Logistic
Secondary
Percentage of Participants With HbA1c on Treatment <7.0 Percentage (%) After 24 Weeks of Treatment
Percentage of participants with HbA1c on treatment \<7.0 percentage (%) after 24 weeks of treatment. Participants with baseline HbA1c \<7.0% were excluded from the analysis.
Time frame: 24 weeks
Population: Full analysis set (FAS) Non-completers considered as failure (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Matching Linagliptin | Percentage of Participants With HbA1c on Treatment <7.0 Percentage (%) After 24 Weeks of Treatment | 8.2 Percentage of participants |
| Linagliptin | Percentage of Participants With HbA1c on Treatment <7.0 Percentage (%) After 24 Weeks of Treatment | 13.9 Percentage of participants |
Comparison: Logistic regression model with terms for treatment and type of insulin as fixed effect and continuous linear covariates baseline HbA1cp-value: 0.243195% CI: [0.673, 4.78]Regression, Logistic