Diabetes Mellitus, Type 2
Conditions
Brief summary
To investigate the efficacy, safety, and tolerability of linagliptin 5 milligrams once a day compared to placebo as as add-on therapy for 24 weeks to stable basal insulin treatment in elderly patients, 60 years of age and older, with Type 2 Diabetes Mellitus and insufficient glycaemic control.Stable background therapy of metformin and/or alpha-glucosidase inhibitors is also allowed. In addition, this trial will assess if linagliptin reduces the risk of hypoglycaemia when added to background basal insulin therapy. The treatment duration of this trial (24 weeks) will enable assessment of the clinically relevant endpoint of a decrease in glycosylated Haemoglobin, a well-accepted measurement of chronic glycaemic control.
Interventions
DRUGplacebo
placebo matching linagliptin 5 mg
DRUGlinagliptin
5 mg once a day
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must sign and date an Informed Consent consistent with International Conference on Harmonisation and Good Clinical Practice guidelines and local regulations prior to any evaluation and participation in the trial. * Male and female patients with a clinical diagnosis of Type 2 Diabetes Mellitus, at the time of Informed Consent, who are: * 60 years of age or older at informed consent or Screen Visit, * taking stable doses of basal or biosimilar basal insulin \[strictly inclusive of: insulin neutral protamine Hagedorn and isophane insulin; Humalog Basal (a suspension of insulin lispro protamine); insulin degludec; insulin detemir; and insulin glargine\] for at least 4 weeks prior to randomisation (Visit 3) with dose adjustments up to a maximum of plus or minus 20% of baseline being allowed, * may or may not be taking metformin immediate release or extended release \[if the patient is taking metformin, stable dose must be maintained for at least twelve weeks without dose adjustments prior to randomisation (Visit 3)\], and * may or may not be taking alpha-glucosidase inhibitors \[acarbose, miglitol, and voglibose; if the patient is taking alpha-glucosidase inhibitors, stable dose must be maintained for at least twelve weeks without dose adjustments prior to randomisation (Visit 3)\]. * Patients must have an glycosylated Haemoglobin of 7.0% (53 millimoles per mole) to 10.0% (86 millimoles per mole) at the first visit (Screen). * Patients must have a Body Mass Index of 45 kilogram/meter squared or less at the Screen Visit. * In the investigator's opinion, patients must be reliable, compliant, and agree to cooperate with all planned future trial evaluations as explained in detail during the informed consent process and to be able to perform them.
Exclusion criteria
* Impaired cognitive ability as supported by the Saint Louis University Mental Status Examination, additional assessment if necessary, and verified by the investigator at the Screen Visit. * Depressed mood as supported by a score of 10 or more on the Patient Health Questionnaire at the Screen Visit. * Type 1 Diabetes Mellitus as determined by past medical records and history. * Acute coronary syndrome (non-ST Elevation Myocardial Infarction, ST Elevation Myocardial Infarction, and/or unstable angina pectoris), stroke or transient ischemic attack within 3 months prior to Screen Visit. * Indication of liver disease determined during Screen and/or Run-In Period, defined by a serum level above 3 times the upper limit of normal in any of the following: alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase. * Bariatric, gastric bypass, and other gastrointestinal procedures or surgeries (including all types of gastric banding, restriction, and/or LapBand) with the objective of promoting weight loss within the past two years at Screen Visit. * Medical history of cancer (except for resected non-invasive basal or squamous cell carcinoma) and/or treatment for cancer within the last 5 years. * Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells (malaria, babesiosis, haemolytic anaemia).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) After 24 Weeks of Treatment. | Baseline and Week 24 | This outcome has measured difference between HbA1c values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication. HbA1c is a form of hemoglobin, a blood pigment that carries oxygen, which is bound to glucose. The term HbA1c also refers to glycated hemoglobin. High levels of HbA1c (Normal range is less than 6%) indicate poorer control of diabetes than level in normal range. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Experiencing at Least One Hypoglycaemia Accompanied by a Prespecified Glucose Value. | 24 weeks | Hypoglycaemia accompanied by a prespecified glucose value is defined as any investigator reported hypoglycaemia (event or AE) with a reported blood glucose level of less than 54 milligram/deciLitre (3.0 millimole/Litre) or any investigator reported symptomatic hypoglycaemic AE with a reported blood glucose level of less or equal 70 milligram/deciLitre (3.9millimole/Litre) or any severe hypoglycaemic AE. Severe hypoglycaemia is an event that requires the assistance of another person to actively administer carbohydrates or glucagon because the patient is unable to take the substance on his or her own. The confidence intervals mentioned in measure of dispersion are exact 95% confidence interval by Clopper and Pearson. The percentage of patients with at least one hypoglycaemia accompanied by a glucose value less than 54mg/dL alone has also represented separately according American Diabetes Association definition of clinically significant hypoglycaemia. |
| Percentage of Patients With HbA1c<8.0% | 24 weeks | This is the percentage of patients with HbA1c on treatment \<8.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson. |
| Percentage of Patients With HbA1c on Treatment <7.0% | 24 weeks | This is the percentage of patients with HbA1c on treatment \<7.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson. |
| Percentage of Patients With HbA1c Lowering by at Least 0.5%. | 24 weeks | The percentage of patients who attained lowering of HbA1c by ≥0.5% from baseline after 24 weeks of treatment were analysed. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson. |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Baseline and Week 24 | This outcome has measured difference between FPG values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication |
Countries
Australia, Belgium, Colombia, Denmark, Finland, Germany, Greece, Ireland, Japan, Mexico, New Zealand, Poland, Romania, South Africa, Spain, United Kingdom, United States
Participant flow
Recruitment details
This was randomised, double blinded, placebo controlled, parallel study. Total 525 patients with type 2 diabetes mellitus (T2DM) and insufficient glycaemic control were screened. 302 patients were randomised into two groups. The trial was extended to 52 weeks for Japanese patients. 102 patients were identified and observed for the extended period.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subject) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Up to 24 Weeks) Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks | 151 |
| Linagliptin 5 Milligram (Up to 24 Weeks) Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks. | 151 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Japanese Patients (Up to 52 Weeks) | Adverse Event | 0 | 0 | 6 | 7 |
| Japanese Patients (Up to 52 Weeks) | Protocol Violation | 0 | 0 | 1 | 0 |
| Japanese Patients (Up to 52 Weeks) | Withdrawal by Subject | 0 | 0 | 1 | 0 |
| Overall Study (Up to 24 Weeks) | Adverse Event | 6 | 6 | 0 | 0 |
| Overall Study (Up to 24 Weeks) | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study (Up to 24 Weeks) | Other than specified | 1 | 0 | 0 | 0 |
| Overall Study (Up to 24 Weeks) | Protocol Violation | 4 | 1 | 0 | 0 |
| Overall Study (Up to 24 Weeks) | Withdrawal by Subject | 3 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo (Up to 24 Weeks) | Linagliptin 5 Milligram (Up to 24 Weeks) | Total |
|---|---|---|---|
| Age, Continuous | 72.5 Years STANDARD_DEVIATION 5.6 | 72.3 Years STANDARD_DEVIATION 5.1 | 72.4 Years STANDARD_DEVIATION 5.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 15 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 132 Participants | 136 Participants | 268 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin A1c (HbA1c) at baseline | 8.1 Percentage of HbA1c (%) STANDARD_DEVIATION 0.7 | 8.2 Percentage of HbA1c (%) STANDARD_DEVIATION 0.8 | 8.2 Percentage of HbA1c (%) STANDARD_DEVIATION 0.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 4 Participants | 11 Participants |
| Race (NIH/OMB) Asian | 52 Participants | 52 Participants | 104 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 8 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 81 Participants | 84 Participants | 165 Participants |
| Sex: Female, Male Female | 60 Participants | 59 Participants | 119 Participants |
| Sex: Female, Male Male | 91 Participants | 92 Participants | 183 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 151 | 2 / 151 | 0 / 50 | 0 / 52 |
| other Total, other adverse events | 58 / 151 | 72 / 151 | 19 / 50 | 37 / 52 |
| serious Total, serious adverse events | 21 / 151 | 19 / 151 | 7 / 50 | 13 / 52 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) After 24 Weeks of Treatment.
This outcome has measured difference between HbA1c values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication. HbA1c is a form of hemoglobin, a blood pigment that carries oxygen, which is bound to glucose. The term HbA1c also refers to glycated hemoglobin. High levels of HbA1c (Normal range is less than 6%) indicate poorer control of diabetes than level in normal range.
Time frame: Baseline and Week 24
Population: Full analysis set observed cases (FAS (OC)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. These analyses used available data as observed while patients were on treatment. All values collected after a patient started rescue medication were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Up to 24 Weeks) | Change From Baseline in Hemoglobin A1c (HbA1c) After 24 Weeks of Treatment. | -0.38 Percentage (%) of HbA1c | Standard Error 0.07 |
| Linagliptin 5 Milligram (Up to 24 Weeks) | Change From Baseline in Hemoglobin A1c (HbA1c) After 24 Weeks of Treatment. | -1.01 Percentage (%) of HbA1c | Standard Error 0.06 |
p-value: <0.000195% CI: [-0.81, -0.46]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
This outcome has measured difference between FPG values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication
Time frame: Baseline and Week 24
Population: Full analysis set observed cases (FAS (OC)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. These analyses used available data as observed while patients were on treatment. All values collected after a patient started rescue medication were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Up to 24 Weeks) | Change From Baseline in Fasting Plasma Glucose (FPG) | 0.2 milligram/decilitre | Standard Error 3.6 |
| Linagliptin 5 Milligram (Up to 24 Weeks) | Change From Baseline in Fasting Plasma Glucose (FPG) | -11.3 milligram/decilitre | Standard Error 3.3 |
p-value: 0.017895% CI: [-21, -2]Mixed Models Analysis
Secondary
Percentage of Patients Experiencing at Least One Hypoglycaemia Accompanied by a Prespecified Glucose Value.
Hypoglycaemia accompanied by a prespecified glucose value is defined as any investigator reported hypoglycaemia (event or AE) with a reported blood glucose level of less than 54 milligram/deciLitre (3.0 millimole/Litre) or any investigator reported symptomatic hypoglycaemic AE with a reported blood glucose level of less or equal 70 milligram/deciLitre (3.9millimole/Litre) or any severe hypoglycaemic AE. Severe hypoglycaemia is an event that requires the assistance of another person to actively administer carbohydrates or glucagon because the patient is unable to take the substance on his or her own. The confidence intervals mentioned in measure of dispersion are exact 95% confidence interval by Clopper and Pearson. The percentage of patients with at least one hypoglycaemia accompanied by a glucose value less than 54mg/dL alone has also represented separately according American Diabetes Association definition of clinically significant hypoglycaemia.
Time frame: 24 weeks
Population: Full analysis set observed cases (FAS (OC)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. These analyses used available data as observed while patients were on treatment. All values collected after a patient started rescue medication were excluded from the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Up to 24 Weeks) | Percentage of Patients Experiencing at Least One Hypoglycaemia Accompanied by a Prespecified Glucose Value. | Prespecified glucose value | 23.8 Percentage of patients (%) |
| Placebo (Up to 24 Weeks) | Percentage of Patients Experiencing at Least One Hypoglycaemia Accompanied by a Prespecified Glucose Value. | Glucose value <54 mg/dL | 15.0 Percentage of patients (%) |
| Linagliptin 5 Milligram (Up to 24 Weeks) | Percentage of Patients Experiencing at Least One Hypoglycaemia Accompanied by a Prespecified Glucose Value. | Prespecified glucose value | 30.9 Percentage of patients (%) |
| Linagliptin 5 Milligram (Up to 24 Weeks) | Percentage of Patients Experiencing at Least One Hypoglycaemia Accompanied by a Prespecified Glucose Value. | Glucose value <54 mg/dL | 16.8 Percentage of patients (%) |
Comparison: For any hypoglycemia event accompanied by prespecified glucose valuep-value: 0.159495% CI: [0.861, 2.491]Regression, Logistic
Comparison: For glucose value \< 54mg/dL according American Diabetes Association definition of clinically significant hypoglycaemiap-value: 0.67295% CI: [0.604, 2.188]Regression, Logistic
Secondary
Percentage of Patients With HbA1c<8.0%
This is the percentage of patients with HbA1c on treatment \<8.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.
Time frame: 24 weeks
Population: Full analysis set (Non-completers considered failure)(FAS (NCF)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. This analyses regarded missing values for binary efficacy endpoints as failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Up to 24 Weeks) | Percentage of Patients With HbA1c<8.0% | 40.2 Percentage of patients (%) |
| Linagliptin 5 Milligram (Up to 24 Weeks) | Percentage of Patients With HbA1c<8.0% | 70.1 Percentage of patients (%) |
p-value: <0.000195% CI: [2.468, 10.206]Regression, Logistic
Secondary
Percentage of Patients With HbA1c Lowering by at Least 0.5%.
The percentage of patients who attained lowering of HbA1c by ≥0.5% from baseline after 24 weeks of treatment were analysed. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.
Time frame: 24 weeks
Population: Full analysis set non-completers considered failure (FAS (NCF)): Includes all patients randomised in the treated set who had a baseline and at least one on-treatment HbA1c value. This analyses regarded missing values for binary efficacy endpoints as failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Up to 24 Weeks) | Percentage of Patients With HbA1c Lowering by at Least 0.5%. | 37.4 Percentage of patients (%) |
| Linagliptin 5 Milligram (Up to 24 Weeks) | Percentage of Patients With HbA1c Lowering by at Least 0.5%. | 69.1 Percentage of patients (%) |
p-value: <0.000195% CI: [2.302, 6.048]Regression, Logistic
Secondary
Percentage of Patients With HbA1c on Treatment <7.0%
This is the percentage of patients with HbA1c on treatment \<7.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.
Time frame: 24 weeks
Population: Full analysis set non-completers considered failure (FAS (NCF)): Includes all patients randomised in the treated set who had a baseline and at least one on-treatment HbA1c value. This analyses regarded missing values for binary efficacy endpoints as failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Up to 24 Weeks) | Percentage of Patients With HbA1c on Treatment <7.0% | 14.6 Percentage of Patients (%) |
| Linagliptin 5 Milligram (Up to 24 Weeks) | Percentage of Patients With HbA1c on Treatment <7.0% | 37.8 Percentage of Patients (%) |
p-value: <0.000195% CI: [2.485, 8.848]Regression, Logistic