Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The purpose of the trial is to investigate the efficacy and safety of liraglutide in combination with insulin therapy compared to insulin alone in Japanese subjects with type 2 diabetes mellitus. Subjects will remain on their pre-trial insulin therapy.
Interventions
DRUGliraglutide
Liraglutide administered subcutaneously (s.c., under the skin) for 36 weeks combined with insulin therapy.
DRUGplacebo
Liraglutide placebo administered subcutaneously (s.c., under the skin) for 36 weeks combined with insulin therapy.
DRUGinsulin
All subjects will continue their pre-trial insulin therapy (basal, premixed or basal-bolus regimen) during the trial. Insulin dose is fixed for the first 16 weeks and for the subsequent 20 weeks, insulin dose is individually adjusted.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus (diagnosed clinically) for at least 6 months * Current insulin therapy (basal insulin, premixed insulin or basal-bolus regimen) in addition to diet and exercise therapy for at least 12 weeks prior to trial start. Their therapy is stable and fluctuation of total daily insulin dose is within plus/minus 20% for at least 12 weeks prior to trial start and current total daily insulin dose equal to or greater than 10 (I)U/day * Glycosylated haemoglobin (HbA1c) between 7.5 and 11.0% (both inclusive) * Body Mass Index (BMI) below 45.0 kg/m\^2
Exclusion criteria
* Anticipated change in concomitant medication known to interfere significantly with glucose metabolism, such as, but not limited to systemic corticosteroids, beta-antagonists or monoamine oxidase (MAO) inhibitors * Recurrent severe hypoglycaemia (more than 1 severe hypoglycaemic episode during last 12 months) or hypoglycaemic unawareness as judged by the investigator or hospitalisation for diabetic ketoacidosis during the previous 6 months * Known proliferative retinopathy or maculopathy requiring treatment according to the investigator * Treatment with glucagon-like peptide-1 (GLP-1) receptor agonist within 12 weeks prior to screening * Treatment with any oral antidiabetic drugs (OADs) within 12 weeks prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 16 | Week 0, Week 16 | Estimated mean change from baseline in HbA1c after 16 Weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 | Week 0, Week 16 | Estimated mean change from baseline in FPG after 16 Weeks of treatment. |
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 36 | Week 0, Week 36 | Estimated mean change from baseline in FPG after 36 Weeks of treatment. |
| Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 16 | Week 0, Week 16 | Estimated mean change from baseline in mean PG of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 16 Weeks of treatment. |
| Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 36 | Week 0, Week 36 | Estimated mean change from baseline in mean PG of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 36 Weeks of treatment. |
| Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 16 | Week 0, Week 16 | Estimated mean change from baseline in mean prandial PG increment of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 16 Weeks of treatment. |
| Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 36 | Week 0, Week 36 | Estimated mean change from baseline in HbA1c after 36 Weeks of treatment |
| Change in Body Weight From Baseline to Week 16 | Week 0, Week 16 | Estimated mean change in body weight after 16 Weeks of treatment |
| Change in Body Weight From Baseline to Week 36 | Week 0, Week 36 | Estimated mean change in body weight after 36 Weeks of treatment |
| Number of Adverse Events (AEs) | Week 0 to Week 36 (inclusive) | An AE was defined as treatment emergent if the onset date 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. |
| Number of Confirmed Hypoglycaemic Episodes | Week 0 to week 36 (inclusive) | A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and until the last day on randomised treatment. Confirmed hypoglycaemic episode was defined as hypoglycaemic episodes categorised to severe and/or minor hypoglycaemic episodes. Confirmed hypoglycaemia: subject unable to treat himself/herself and/or have a recorded PG \< 3.1 mmol/L (56 mg/dL). Minor: PG \< 3.1 mmol/L (56 mg/dL). |
| Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 36 | Week 0, Week 36 | Estimated mean change from baseline in mean prandial PG increment of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 36 Weeks of treatment. |
Countries
Japan
Participant flow
Recruitment details
This trial was conducted at 23 sites in Japan.
Pre-assignment details
Subjects on pre-trial insulin (basal insulin \[intermediate acting human insulin, intermediate acting insulin analogue or long-acting insulin analogue\], premixed insulin or basal-bolus regimen) therapy for at least 12 weeks prior to screening.
Participants by arm
| Arm | Count |
|---|---|
| Lira + Insulin Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks.
All subjects continued their pre-trial insulin therapy (basal: once daily \[OD\] or twice daily \[BID\], premixed: OD or BID or basal-bolus regimen \[basal: OD or BID and bolus: three times a day\]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted. | 127 |
| Placebo + Insulin Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks.
All subjects continued their pre-trial insulin therapy (basal: once daily \[OD\] or twice daily \[BID\], premixed: OD or BID or basal-bolus regimen \[basal: OD or BID and bolus: three times a day\]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted. | 130 |
| Total | 257 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | unclassified | 4 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Lira + Insulin | Placebo + Insulin | Total |
|---|---|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 11 | 59.8 years STANDARD_DEVIATION 11.3 | 60.5 years STANDARD_DEVIATION 11.2 |
| Body Weight | 67.7 kg STANDARD_DEVIATION 15.2 | 65.9 kg STANDARD_DEVIATION 13 | 66.8 kg STANDARD_DEVIATION 14.1 |
| Fasting Plasma Glucose (FPG) | 8.51 mmol/L STANDARD_DEVIATION 2.42 | 8.79 mmol/L STANDARD_DEVIATION 2.51 | 8.65 mmol/L STANDARD_DEVIATION 2.47 |
| Glycosylated Haemoglobin (HbA1c) | 8.8 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.8 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.8 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 |
| Sex: Female, Male Female | 58 Participants | 55 Participants | 113 Participants |
| Sex: Female, Male Male | 69 Participants | 75 Participants | 144 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 93 / 127 | 69 / 130 |
| serious Total, serious adverse events | 6 / 127 | 4 / 130 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 16
Estimated mean change from baseline in HbA1c after 16 Weeks of treatment.
Time frame: Week 0, Week 16
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 16 as subject was withdrawn from the trial before sampling for any efficacy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 16 | -1.73 percentage of glycosylated haemoglobin | Standard Error 0.06 |
| Placebo + Insulin | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 16 | -0.43 percentage of glycosylated haemoglobin | Standard Error 0.06 |
p-value: <0.000195% CI: [-1.47, -1.13]ANCOVA
Secondary
Change in Body Weight From Baseline to Week 16
Estimated mean change in body weight after 16 Weeks of treatment
Time frame: Week 0, Week 16
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 16 as subject was withdrawn from the trial before sampling for any efficacy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Body Weight From Baseline to Week 16 | -0.42 kg | Standard Error 0.14 |
| Placebo + Insulin | Change in Body Weight From Baseline to Week 16 | -0.28 kg | Standard Error 0.14 |
p-value: 0.480695% CI: [-0.54, 0.25]ANCOVA
Secondary
Change in Body Weight From Baseline to Week 36
Estimated mean change in body weight after 36 Weeks of treatment
Time frame: Week 0, Week 36
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 36 as subject was withdrawn from the trial before sampling for any efficacy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Body Weight From Baseline to Week 36 | 0.17 kg | Standard Error 0.2 |
| Placebo + Insulin | Change in Body Weight From Baseline to Week 36 | 0.52 kg | Standard Error 0.2 |
p-value: 0.207495% CI: [-0.91, 0.2]ANCOVA
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16
Estimated mean change from baseline in FPG after 16 Weeks of treatment.
Time frame: Week 0, Week 16
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 16 as subject was withdrawn from the trial before sampling for any efficacy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 | -1.31 mmol/L | Standard Error 0.17 |
| Placebo + Insulin | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 | -0.48 mmol/L | Standard Error 0.17 |
p-value: <0.000695% CI: [-1.3, -0.36]ANCOVA
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline to Week 36
Estimated mean change from baseline in FPG after 36 Weeks of treatment.
Time frame: Week 0, Week 36
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 36 as subject was withdrawn from the trial before sampling for any efficacy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 36 | -1.55 mmol/L | Standard Error 0.16 |
| Placebo + Insulin | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 36 | -1.29 mmol/L | Standard Error 0.16 |
p-value: 0.251195% CI: [-0.7, 0.18]ANCOVA
Secondary
Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 36
Estimated mean change from baseline in HbA1c after 36 Weeks of treatment
Time frame: Week 0, Week 36
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 36 as subject was withdrawn from the trial before sampling for any efficacy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 36 | -1.68 percentage of glycosylated haemoglobin | Standard Error 0.06 |
| Placebo + Insulin | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 36 | -0.88 percentage of glycosylated haemoglobin | Standard Error 0.06 |
p-value: <0.000195% CI: [-0.99, -0.63]ANCOVA
Secondary
Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 16
Estimated mean change from baseline in mean PG of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 16 Weeks of treatment.
Time frame: Week 0, Week 16
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 9 subjects did not contribute to the statistical analysis at Week 16 due to missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 16 | -2.41 mmol/L | Standard Error 0.18 |
| Placebo + Insulin | Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 16 | -0.53 mmol/L | Standard Error 0.18 |
p-value: <0.000195% CI: [-2.37, -1.38]ANCOVA
Secondary
Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 36
Estimated mean change from baseline in mean PG of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 36 Weeks of treatment.
Time frame: Week 0, Week 36
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 8 subjects did not contribute to the statistical analysis at Week 36 due to missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 36 | -2.65 mmol/L | Standard Error 0.16 |
| Placebo + Insulin | Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 36 | -1.37 mmol/L | Standard Error 0.16 |
p-value: <0.000195% CI: [-1.73, -0.83]ANCOVA
Secondary
Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 16
Estimated mean change from baseline in mean prandial PG increment of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 16 Weeks of treatment.
Time frame: Week 0, Week 16
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 9 subjects did not contribute to the statistical analysis at Week 16 due to missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 16 | -1.34 mmol/L | Standard Error 0.17 |
| Placebo + Insulin | Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 16 | -0.61 mmol/L | Standard Error 0.17 |
p-value: 0.002395% CI: [-1.2, -0.26]ANCOVA
Secondary
Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 36
Estimated mean change from baseline in mean prandial PG increment of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 36 Weeks of treatment.
Time frame: Week 0, Week 36
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 13 subjects did not contribute to the statistical analysis at Week 36 due to missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira + Insulin | Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 36 | -1.34 mmol/L | Standard Error 0.21 |
| Placebo + Insulin | Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 36 | -0.94 mmol/L | Standard Error 0.21 |
p-value: 0.178795% CI: [-0.97, 0.18]ANCOVA
Secondary
Number of Adverse Events (AEs)
An AE was defined as treatment emergent if the onset date 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.
Time frame: Week 0 to Week 36 (inclusive)
Population: Safety analysis set includes all subjects who received at least one dose of the trial products.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lira + Insulin | Number of Adverse Events (AEs) | Adverse Events | 449 Events/100 years of patient exposure |
| Lira + Insulin | Number of Adverse Events (AEs) | Moderate Adverse Events | 8 Events/100 years of patient exposure |
| Lira + Insulin | Number of Adverse Events (AEs) | Severe Adverse Events | 5 Events/100 years of patient exposure |
| Lira + Insulin | Number of Adverse Events (AEs) | Mild Adverse Events | 436 Events/100 years of patient exposure |
| Lira + Insulin | Number of Adverse Events (AEs) | Serious Adverse Events | 8 Events/100 years of patient exposure |
| Placebo + Insulin | Number of Adverse Events (AEs) | Mild Adverse Events | 335 Events/100 years of patient exposure |
| Placebo + Insulin | Number of Adverse Events (AEs) | Adverse Events | 350 Events/100 years of patient exposure |
| Placebo + Insulin | Number of Adverse Events (AEs) | Serious Adverse Events | 5 Events/100 years of patient exposure |
| Placebo + Insulin | Number of Adverse Events (AEs) | Severe Adverse Events | 1 Events/100 years of patient exposure |
| Placebo + Insulin | Number of Adverse Events (AEs) | Moderate Adverse Events | 14 Events/100 years of patient exposure |
Secondary
Number of Confirmed Hypoglycaemic Episodes
A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and until the last day on randomised treatment. Confirmed hypoglycaemic episode was defined as hypoglycaemic episodes categorised to severe and/or minor hypoglycaemic episodes. Confirmed hypoglycaemia: subject unable to treat himself/herself and/or have a recorded PG \< 3.1 mmol/L (56 mg/dL). Minor: PG \< 3.1 mmol/L (56 mg/dL).
Time frame: Week 0 to week 36 (inclusive)
Population: Safety analysis set includes all subjects who received at least one dose of the trial products.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lira + Insulin | Number of Confirmed Hypoglycaemic Episodes | 146 Episodes/100 years of patient exposure |
| Placebo + Insulin | Number of Confirmed Hypoglycaemic Episodes | 187 Episodes/100 years of patient exposure |