Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial was conducted in Japan. The aim of this trial was to evaluate the safety and efficacy of once daily administration of liraglutide in combination with an oral anti-diabetic drug (OAD) in Japanese subjects with type 2 diabetes who are insufficiently controlled on OAD monotherapy. All subjects will continue their pre-trial OAD (either glinide, metformin, alpha-glucosidase inhibitor or thiazolidinedione) during the trial at unchanged type and dose.
Interventions
DRUGliraglutide
0.9 mg/day liraglutide was injected once daily subcutaneously (s.c., under the skin).
DRUGoral anti-diabetic drug
An additional oral anti-diabetic drug (OAD) with a different mechanism of action than the pre-trial OAD. The type and dosage of the additional OAD should be chosen by the investigator within the Japanese labelled dose.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Informed consent obtained before any trial-related activities (trial-related activities are any procedures that would not have been performed during normal management of the subject.) * Japanese subjects with type 2 diabetes on monotherapy with an OAD (either glinide, metformin, a-glucosidase inhibitor or thiazolidinedione) within approved Japanese labelling in addition to diet and exercise therapy. Total daily dose and type of drug should have remained unchanged for at least 8 weeks prior to Visit 1 * Type 2 diabetes mellitus (clinically diagnosed) for at least 6 months * HbA1c between 7.0-10.0% (both inclusive) * Body Mass Index (BMI) below 40.0 kg/m\^2 * Outpatients who have no plans for an educational hospitalisation for the purpose of glycaemic control. However, hospitalisation for training of self-injection from Visit 2 that is for no longer than one week is allowed * Subjects able and willing to perform self-monitoring of plasma glucose (SMPG)
Exclusion criteria
* Subjects with known or previous malignant tumor and are strongly suspected of recurrence (except basal cell skin cancer or squamous cell skin cancer) * Calcitonin above or equal to 160 pg/mL * Personal history of non-familial medullary thyroid carcinoma * Family or personal history of multiple endocrine neoplasia type 2 (MEN-2) or familial medullary thyroid carcinoma (FMTC) * History of chronic pancreatitis or idiopathic acute pancreatitis * Recurrent severe hypoglycaemia (more than 1 severe hypoglycaemic event during the last 12 months) or hypoglycaemic unawareness as judged by the investigator or hospitalisation for diabetic ketoacidosis during the previous 6 months * Treatment with GLP-1 receptor agonist or dipeptidyl peptidase 4 (DPP-4) inhibitor within 12 weeks prior to Visit 1 * Having contraindications to liraglutide and any of the OADs (according to Japanese labelling)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment Emergent Adverse Events (AEs) | Week 0 to Week 52 + 7 days | Adverse events were defined as events occurring after administration of trial product and no later than 7 days after last day of treatment. Severe AEs: considerable interference with subject's daily activities. Moderate AEs: Marked symptoms, moderate interference with the subject's daily activities. Mild AEs: No or transient symptoms, no interference with the subject's daily activities. Serious AEs: AEs that resulted in any of the following: death, a life-threatening experience, hospitalization/prolongation of existing hospitalization, persistent/significant disability, and congenital anomaly. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Confirmed Hypoglycaemic Episodes | Week 0 to Week 52 | Confirmed hypoglycaemic episodes consisted of the pool of episodes of severe hypoglycaemia as well as minor hypoglycaemic episodes \[An episode with symptoms consistent with hypoglycaemia with confirmation by plasma glucose \<3.1 mmol/L (56 mg/dL) or full blood glucose \<2.8 mmol/L (50 mg/dL) and which is handled by the subject himself or herself or any asymptomatic PG value \<3.1 mmol/L (56 mg/dL) or full blood glucose value \<2.8 mmol/L (50 mg/dL)\] with a confirmed plasma glucose value of less than 3.1 mmol/L (56 mg/dL). |
| Change in HbA1c From Baseline to Week 52 | Week 0, week 52 | Estimated mean change in HbA1c from baseline after 52 Weeks of treatment |
| Change in FPG From Baseline to Week 52 | Week 0, week 52 | Estimated mean change from baseline in FPG after 52 Weeks of treatment |
Countries
Japan
Participant flow
Recruitment details
The trial was conducted at 36 sites in Japan.
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide 0.9 mg/Day Liraglutide 0.9 mg/day was injected subcutaneously, once daily in morning or evening in addition to unchanged pre-trial oral anti-diabetic drug (OAD) (either glinide, metformin, α-glucosidase inhibitor or thiazolidinedione) for 52 weeks. Liraglutide was started at 0.3 mg/day and dose was escalated to maximum dose level of 0.9 mg/day by weekly increment of 0.3 mg. | 240 |
| Additional OAD Subject's received additional OAD to pre-trial OAD. The type and dosage of additional OAD was chosen based on each individual's glycaemic control by the investigator as per Japanese labelling. | 120 |
| Total | 360 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 4 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Unclassified | 11 | 3 |
| Overall Study | Withdrawal Criteria | 1 | 0 |
Baseline characteristics
| Characteristic | Liraglutide 0.9 mg/Day | Additional OAD | Total |
|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 11.6 | 59.2 years STANDARD_DEVIATION 10.2 | 59.5 years STANDARD_DEVIATION 11.1 |
| Fasting plasma glucose (FPG) | 8.68 mmol/L STANDARD_DEVIATION 1.61 | 8.96 mmol/L STANDARD_DEVIATION 1.82 | 8.77 mmol/L STANDARD_DEVIATION 1.69 |
| Glycosylated haemoglobin (HbA1c) | 8.1 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.1 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.1 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 |
| Sex: Female, Male Female | 58 Participants | 40 Participants | 98 Participants |
| Sex: Female, Male Male | 182 Participants | 80 Participants | 262 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 161 / 240 | 77 / 120 |
| serious Total, serious adverse events | 11 / 240 | 10 / 120 |
Outcome results
Primary
Incidence of Treatment Emergent Adverse Events (AEs)
Adverse events were defined as events occurring after administration of trial product and no later than 7 days after last day of treatment. Severe AEs: considerable interference with subject's daily activities. Moderate AEs: Marked symptoms, moderate interference with the subject's daily activities. Mild AEs: No or transient symptoms, no interference with the subject's daily activities. Serious AEs: AEs that resulted in any of the following: death, a life-threatening experience, hospitalization/prolongation of existing hospitalization, persistent/significant disability, and congenital anomaly.
Time frame: Week 0 to Week 52 + 7 days
Population: Safety analysis set included all subjects who received at least one dose of the trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide 0.9 mg/Day | Incidence of Treatment Emergent Adverse Events (AEs) | Mild AEs | 345 Events/100 years of patient exposure |
| Liraglutide 0.9 mg/Day | Incidence of Treatment Emergent Adverse Events (AEs) | Severe AEs | 2 Events/100 years of patient exposure |
| Liraglutide 0.9 mg/Day | Incidence of Treatment Emergent Adverse Events (AEs) | Moderate AEs | 14 Events/100 years of patient exposure |
| Liraglutide 0.9 mg/Day | Incidence of Treatment Emergent Adverse Events (AEs) | Serious AEs | 5 Events/100 years of patient exposure |
| Liraglutide 0.9 mg/Day | Incidence of Treatment Emergent Adverse Events (AEs) | All AEs | 361 Events/100 years of patient exposure |
| Additional OAD | Incidence of Treatment Emergent Adverse Events (AEs) | Serious AEs | 9 Events/100 years of patient exposure |
| Additional OAD | Incidence of Treatment Emergent Adverse Events (AEs) | All AEs | 331 Events/100 years of patient exposure |
| Additional OAD | Incidence of Treatment Emergent Adverse Events (AEs) | Mild AEs | 321 Events/100 years of patient exposure |
| Additional OAD | Incidence of Treatment Emergent Adverse Events (AEs) | Moderate AEs | 9 Events/100 years of patient exposure |
| Additional OAD | Incidence of Treatment Emergent Adverse Events (AEs) | Severe AEs | 2 Events/100 years of patient exposure |
Secondary
Change in FPG From Baseline to Week 52
Estimated mean change from baseline in FPG after 52 Weeks of treatment
Time frame: Week 0, week 52
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products and missing data were imputed using last observation carried forward (LOCF). One subject did not contribute to the statistical analysis at Week 52.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 0.9 mg/Day | Change in FPG From Baseline to Week 52 | -1.55 mmol/L | Standard Error 0.09 |
| Additional OAD | Change in FPG From Baseline to Week 52 | -1.24 mmol/L | Standard Error 0.12 |
p-value: 0.045895% CI: [-0.6, -0.01]ANOVA
Secondary
Change in HbA1c From Baseline to Week 52
Estimated mean change in HbA1c from baseline after 52 Weeks of treatment
Time frame: Week 0, week 52
Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products and missing data were imputed using last observation carried forward (LOCF). One subject did not contribute to the statistical analysis at Week 52.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 0.9 mg/Day | Change in HbA1c From Baseline to Week 52 | -1.21 percentage of glycosylated haemoglobin | Standard Error 0.05 |
| Additional OAD | Change in HbA1c From Baseline to Week 52 | -0.94 percentage of glycosylated haemoglobin | Standard Error 0.07 |
p-value: 0.002695% CI: [-0.44, -0.09]ANOVA
Secondary
Number of Confirmed Hypoglycaemic Episodes
Confirmed hypoglycaemic episodes consisted of the pool of episodes of severe hypoglycaemia as well as minor hypoglycaemic episodes \[An episode with symptoms consistent with hypoglycaemia with confirmation by plasma glucose \<3.1 mmol/L (56 mg/dL) or full blood glucose \<2.8 mmol/L (50 mg/dL) and which is handled by the subject himself or herself or any asymptomatic PG value \<3.1 mmol/L (56 mg/dL) or full blood glucose value \<2.8 mmol/L (50 mg/dL)\] with a confirmed plasma glucose value of less than 3.1 mmol/L (56 mg/dL).
Time frame: Week 0 to Week 52
Population: Safety analysis set includes all subjects who received at least one dose of the trial product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide 0.9 mg/Day | Number of Confirmed Hypoglycaemic Episodes | 7 episodes |
| Additional OAD | Number of Confirmed Hypoglycaemic Episodes | 2 episodes |