Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia, Europe and North and South America. The aim of the trial is to investigate the effect of liraglutide versus placebo when added to basal insulin analogues with or without metformin in subjects with type 2 diabetes.
Interventions
DRUGliraglutide
Maximum 1.8 mg administered s.c. (subcutaneously, under the skin) once daily in addition to the subject's stable pre-trial basal insulin analogue regimen plus/minus metformin.
DRUGplacebo
Placebo administered s.c. (subcutaneously, under the skin) once daily in addition to the subject's stable pre-trial basal insulin analogue regimen plus/minus metformin.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with type 2 diabetes for at least 180 days prior to screening and treated with stable basal insulin analogue dose of minimum 20 U/day with or without stable metformin equal to or above 1500 mg/day for at least 8 weeks prior to screening (defined as insulin adjustments less than 10% during the past 8 weeks as assessed by the investigator) * HbA1c (glycosylated haemoglobin A1c) 7.0-10.0% (both inclusive) * Body mass index (BMI) 20-45 kg/m\^2 (both inclusive)
Exclusion criteria
* Female of child-bearing potential who is pregnant, breast-feeding or intending to become pregnant * Recurrent severe hypoglycaemic episodes or hypoglycaemic unawareness * Treatment with glucose-lowering agent(s) other than stated in the inclusion criteria in a period of 12 weeks prior to screening * Impaired liver or renal function * Uncontrolled treated or untreated hypertension (systolic blood pressure (SBP) equal to or above 180 mmHg and/or diastolic blood pressure (DBP) equal to or above 100 mmHg) * Any clinically significant disorder, except for conditions associated with type 2 diabetes history which in the investigator's opinion could interfere with results of the trial * Known or suspected abuse of alcohol or narcotics
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 26 | Week 0 to Week 26 | The estimated mean change from baseline in HbA1c after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Self-Measured Plasma Glucose (SMPG) of 7-Point Profile From Baseline to Week 26 | Week 0 to Week 26 | The estimated mean change from baseline in mean SMPG of 7-point profile (7-points were before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime) after 26 weeks of treatment. |
| Change in Body Weight From Baseline to Week 26 | Week 0 to Week 26 | The estimated mean change in body weight after 26 weeks of treatment. |
| Number of Subjects Achieving HbA1c Below 7.0% (American Diabetes Association [ADA] Target) | At Week 26 | Number of subjects achieving HbA1c below 7.0% (American Diabetes Association \[ADA\] target) after 26 weeks of treatment |
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 | Week 0 to Week 26 | The estimated mean change from baseline in FPG after 26 weeks of treatment. |
| Number of Adverse Events (AEs) During The Randomised Treatment Period | Week 0 to Week 26 + 7 days follow up | An AE was defined as treatment emergent if the onset date (or increase in severity) was on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. The adverse events were categorised as 'serious' and 'non-serious' adverse events. Adverse events were also categorised according to the severity as 'mild', 'moderate' and 'severe' adverse events. |
| Number of Minor Hypoglycaemic Episodes During The Randomised Treatment Period | Week 0 to Week 26 + 7 days follow up | A minor hypoglycaemic episode was defined as either, (a) an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose \<2.8 mmol/L (50 mg/dL) or plasma glucose \<3.1 mmol/L (56 mg/dL) that was handled by the subject him/herself or (b) any asymptomatic blood glucose value \<2.8 mmol/L (50 mg/dL) or plasma glucose value \<3.1 mmol/L (56 mg/dL). |
| Number of Severe Hypoglycaemic Episodes During The Randomised Treatment Period | Week 0 to Week 26 + 7 days follow up | Severe hypoglycaemia episode was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. |
| Number of Subjects Achieving HbA1c Below or Equal to 6.5% (American Association of Clinical Endocrinologists [AACE] Target) | At Week 26 | Number of subjects achieving HbA1c below or equal to 6.5% (American Association of Clinical Endocrinologists \[AACE\] target) after 26 weeks of treatment. |
Countries
Argentina, Canada, Finland, Germany, India, Mexico, Netherlands, Serbia, United States
Participant flow
Recruitment details
The trial was conducted at 76 sites in 9 countries i.e. 3 sites in Argentina; 9 sites in Canada; 5 sites in Finland; 9 sites in Germany; 9 sites in India; 2 sites in Mexico; 7 sites in Netherlands; 3 sites in Serbia; 29 sites in United States.
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day. | 225 |
| Placebo Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day. | 225 |
| Total | 450 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 3 |
| Overall Study | Protocol Violation | 8 | 7 |
| Overall Study | Unclassified | 3 | 4 |
| Overall Study | Withdrawal Criteria | 12 | 37 |
Baseline characteristics
| Characteristic | Liraglutide | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 9.2 | 57.5 years STANDARD_DEVIATION 11.1 | 58.4 years STANDARD_DEVIATION 10.2 |
| Body Weight | 90.23 kg STANDARD_DEVIATION 19.98 | 91.85 kg STANDARD_DEVIATION 21.33 | 91.04 kg STANDARD_DEVIATION 20.66 |
| Fasting Plasma Glucose (FPG) | 8.32 mmol/L STANDARD_DEVIATION 2.89 | 8.21 mmol/L STANDARD_DEVIATION 2.9 | 8.27 mmol/L STANDARD_DEVIATION 2.89 |
| Glycosylated Haemoglobin (HbA1c) | 8.22 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.81 | 8.28 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.25 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.86 |
| Sex: Female, Male Female | 105 Participants | 89 Participants | 194 Participants |
| Sex: Female, Male Male | 120 Participants | 136 Participants | 256 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 103 / 225 | 46 / 225 |
| serious Total, serious adverse events | 11 / 225 | 7 / 225 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 26
The estimated mean change from baseline in HbA1c after 26 weeks of treatment.
Time frame: Week 0 to Week 26
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 215 subjects in the liraglutide arm and 217 subjects in the placebo arm contributed to the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 26 | -1.30 percentage of glycosylated haemoglobin | Standard Deviation 1.015 |
| Placebo | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 26 | -0.11 percentage of glycosylated haemoglobin | Standard Deviation 1.088 |
Comparison: The null hypothesis of no difference between the two treatment arms with regard to changes from baseline in HbA1c (%) after 26 weeks of randomised treatment was analysed using a mixed model repeated measurements (MMRM) analysis with treatment, country, stratification groups as factors and baseline HbA1c as a covariate, all nested within visit.p-value: <0.000195% CI: [-1.39, -0.99]Mixed Models Analysis
Secondary
Change in Body Weight From Baseline to Week 26
The estimated mean change in body weight after 26 weeks of treatment.
Time frame: Week 0 to Week 26
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 215 subjects in the liraglutide arm and 216 subjects in the placebo arm contributed to the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Body Weight From Baseline to Week 26 | -3.54 kg | Standard Deviation 3.669 |
| Placebo | Change in Body Weight From Baseline to Week 26 | -0.42 kg | Standard Deviation 3.909 |
Comparison: The response was analysed using a mixed model repeated measurements (MMRM) analysis with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit.p-value: <0.000195% CI: [-3.85, -2.37]Mixed Models Analysis
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26
The estimated mean change from baseline in FPG after 26 weeks of treatment.
Time frame: Week 0 to Week 26
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 213 subjects in the liraglutide arm and 217 subjects in the placebo arm contributed to the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 | -1.44 mmol/L | Standard Deviation 2.494 |
| Placebo | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 | -0.16 mmol/L | Standard Deviation 3.006 |
Comparison: The response was analysed using a mixed model repeated measurements (MMRM) analysis with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit.p-value: <0.000195% CI: [-1.7, -0.86]Mixed Models Analysis
Secondary
Change in Mean Self-Measured Plasma Glucose (SMPG) of 7-Point Profile From Baseline to Week 26
The estimated mean change from baseline in mean SMPG of 7-point profile (7-points were before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime) after 26 weeks of treatment.
Time frame: Week 0 to Week 26
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 191 subjects in the liraglutide arm and 196 subjects in the placebo arm contributed to the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Mean Self-Measured Plasma Glucose (SMPG) of 7-Point Profile From Baseline to Week 26 | -2.61 mmol/L | Standard Deviation 2.248 |
| Placebo | Change in Mean Self-Measured Plasma Glucose (SMPG) of 7-Point Profile From Baseline to Week 26 | -1.02 mmol/L | Standard Deviation 3.061 |
Comparison: The response was analysed using a mixed model repeated measurements (MMRM) analysis with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit.p-value: <0.000195% CI: [-2.01, -1.18]Mixed Models Analysis
Secondary
Number of Adverse Events (AEs) During The Randomised Treatment Period
An AE was defined as treatment emergent if the onset date (or increase in severity) was on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. The adverse events were categorised as 'serious' and 'non-serious' adverse events. Adverse events were also categorised according to the severity as 'mild', 'moderate' and 'severe' adverse events.
Time frame: Week 0 to Week 26 + 7 days follow up
Population: Safety analysis set includes all subjects who received at least one dose of the trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide | Number of Adverse Events (AEs) During The Randomised Treatment Period | Adverse Events | 4918 Events/1000 years of patient exposure |
| Liraglutide | Number of Adverse Events (AEs) During The Randomised Treatment Period | Severe Adverse Events | 169 Events/1000 years of patient exposure |
| Liraglutide | Number of Adverse Events (AEs) During The Randomised Treatment Period | Serious Adverse Events | 149 Events/1000 years of patient exposure |
| Liraglutide | Number of Adverse Events (AEs) During The Randomised Treatment Period | Moderate Adverse Events | 1274 Events/1000 years of patient exposure |
| Liraglutide | Number of Adverse Events (AEs) During The Randomised Treatment Period | Mild Adverse Events | 3474 Events/1000 years of patient exposure |
| Placebo | Number of Adverse Events (AEs) During The Randomised Treatment Period | Moderate Adverse Events | 1060 Events/1000 years of patient exposure |
| Placebo | Number of Adverse Events (AEs) During The Randomised Treatment Period | Mild Adverse Events | 2575 Events/1000 years of patient exposure |
| Placebo | Number of Adverse Events (AEs) During The Randomised Treatment Period | Adverse Events | 3737 Events/1000 years of patient exposure |
| Placebo | Number of Adverse Events (AEs) During The Randomised Treatment Period | Serious Adverse Events | 101 Events/1000 years of patient exposure |
| Placebo | Number of Adverse Events (AEs) During The Randomised Treatment Period | Severe Adverse Events | 101 Events/1000 years of patient exposure |
Secondary
Number of Minor Hypoglycaemic Episodes During The Randomised Treatment Period
A minor hypoglycaemic episode was defined as either, (a) an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose \<2.8 mmol/L (50 mg/dL) or plasma glucose \<3.1 mmol/L (56 mg/dL) that was handled by the subject him/herself or (b) any asymptomatic blood glucose value \<2.8 mmol/L (50 mg/dL) or plasma glucose value \<3.1 mmol/L (56 mg/dL).
Time frame: Week 0 to Week 26 + 7 days follow up
Population: Safety analysis set includes all subjects who received at least one dose of the trial products.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide | Number of Minor Hypoglycaemic Episodes During The Randomised Treatment Period | 126 Events/100 years of patient exposure |
| Placebo | Number of Minor Hypoglycaemic Episodes During The Randomised Treatment Period | 83 Events/100 years of patient exposure |
Secondary
Number of Severe Hypoglycaemic Episodes During The Randomised Treatment Period
Severe hypoglycaemia episode was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions.
Time frame: Week 0 to Week 26 + 7 days follow up
Population: Safety analysis set includes all subjects who received at least one dose of the trial products.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide | Number of Severe Hypoglycaemic Episodes During The Randomised Treatment Period | 0 Events/100 years of patient exposure |
| Placebo | Number of Severe Hypoglycaemic Episodes During The Randomised Treatment Period | 0 Events/100 years of patient exposure |
Secondary
Number of Subjects Achieving HbA1c Below 7.0% (American Diabetes Association [ADA] Target)
Number of subjects achieving HbA1c below 7.0% (American Diabetes Association \[ADA\] target) after 26 weeks of treatment
Time frame: At Week 26
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 211 subjects in the liraglutide arm and 217 subjects in the placebo arm contributed to the statistical analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide | Number of Subjects Achieving HbA1c Below 7.0% (American Diabetes Association [ADA] Target) | 59.24 percentage of subjects |
| Placebo | Number of Subjects Achieving HbA1c Below 7.0% (American Diabetes Association [ADA] Target) | 14.02 percentage of subjects |
Comparison: This endpoint was analysed using a logistic regression model with treatment and stratification factors as fixed factors and the HbA1c value at baseline as a covariate. Subjects previously treated with insulin detemir without the use of metformin were not included in the analysis due to the small size of the stratum.p-value: <0.000195% CI: [5.45, 14.59]Regression, Logistic
Secondary
Number of Subjects Achieving HbA1c Below or Equal to 6.5% (American Association of Clinical Endocrinologists [AACE] Target)
Number of subjects achieving HbA1c below or equal to 6.5% (American Association of Clinical Endocrinologists \[AACE\] target) after 26 weeks of treatment.
Time frame: At Week 26
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product and who provided at least one post-baseline efficacy value. 211 subjects in the liraglutide arm and 217 subjects in the placebo arm contributed to the statistical analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide | Number of Subjects Achieving HbA1c Below or Equal to 6.5% (American Association of Clinical Endocrinologists [AACE] Target) | 42.91 percentage of subjects |
| Placebo | Number of Subjects Achieving HbA1c Below or Equal to 6.5% (American Association of Clinical Endocrinologists [AACE] Target) | 3.60 percentage of subjects |
Comparison: This endpoint was analysed using a logistic regression model with treatment and stratification factors as fixed factors and the HbA1c value at baseline as a covariate. Subjects previously treated with insulin detemir without the use of metformin were not included in the analysis due to the small size of the stratum.p-value: <0.000195% CI: [9.92, 40.84]Regression, Logistic