Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted globally. The aim of the trial is to compare the efficacy and safety of insulin degludec/liraglutide versus insulin glargine in subjects with type 2 diabetes mellitus.
Interventions
DRUGinsulin degludec/liraglutide
Insulin degludec/liraglutide is injected subcutaneously s.c. (under the skin) once daily (OD). Dose individually adjusted. Subjects should continue their pre-trial treatment with metformin.
DRUGinsulin glargine
Insulin glargine is injected subcutaneously s.c. (under the skin) once daily (OD). Dose individually adjusted. Subjects should continue their pre-trial treatment with metformin.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Type 2 diabetes mellitus - HbA1c 7.0-10.0% \[53-86 mmol/mol\] (both inclusive) by central laboratory analysis - Current treatment with insulin glargine for at least 90 days prior to screening - Stable daily dose of insulin glargine between 20 units and 50 units (both inclusive) for at least 56 days prior to screening. Total daily dose should be within the range of 20-50 units, both inclusive, on the day of screening, but individual fluctuations of plus/minus 10 procent within the 56 days prior to screening are acceptable - Stable daily dose of metformin (above or equal to 1500 mg or max tolerated dose) for at least 90 days prior to screening - Body mass index (BMI) below or equal to 40 kg/m\^2
Exclusion criteria
- Any use of oral antidiabetic agents (OADs) (except for metformin) within 90 days prior to Visit 1 (screening) - Current use of any drug (except metformin and insulin glargine) or anticipated change inconcomitant medication, which in the investigator's opinion could interfere with the glucose metabolism (e.g. systemic corticosteroids) - Previous and/or current treatment with any insulin regimen other than basal insulin, e.g. prandial or pre-mixed insulin (short term treatment due to intercurrent illness includinggestational diabetes is allowed at the discretion of the investigator) - Previous and/or current treatment with glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. exenatide, liraglutide) - Impaired liver function, defined as ALAT (alanine aminotransferase) above or equal to 2.5 times upper normal range (UNR) - Impaired renal function defined as serum-creatinine above or equal to 133 micromol/L (above or equal to 1.5 mg/dL) for males and above or equal to 125 micromol/L (1.4 mg/dL) for females, or as allowed according to local contraindications for metformin - Screening calcitonin above or equal to 50 ng/L - Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2) - History of chronic pancreatitis or idiopathic acute pancreatitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0, week 26 | Change from baseline in HbA1c after 26 weeks of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight | Week 0, week 26 | Change from baseline in body weight after 26 weeks of treatment |
| Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | During 26 weeks of treatment | Confirmed hypoglycaemic episodes were defined as either: Severe (i.e., an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) or an episode biochemically confirmed by a plasma glucose value of \<3.1 mmol/L (56 mg/dL), with or without symptoms consistent with hypoglycaemia. |
Countries
Argentina, Australia, Greece, Hungary, Mexico, Russia, Slovakia, South Africa, Spain, United States
Participant flow
Recruitment details
The trial was conducted at 75 sites in 10 countries as follows: Argentina: 5 sites; Australia: 4 sites; Greece: 6 sites, Hungary: 4 sites; Mexico: 5 sites, Russian Federation: 11 sites; Slovakia: 11 sites, South Africa: 4 sites; Spain: 6 sites, United States: 19 sites.
Pre-assignment details
Subjects who were recruited had T2DM and were required to have been on treatment with stable daily dose of insulin glargine between 20 units and 50 units (both inclusive) for at least 56 days prior to screening in combination with a stable daily dose of metformin (≥1500 mg or max tolerated dose) for at least 90 days prior to screening.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Degludec/Liraglutide (IDegLira) Eligible subjects received IDegLira once daily (OD) subcutaneously for a duration of 26 weeks. The starting dose of IDegLira was 16 dose steps (16 units IDeg/0.6 mg liraglutide) and was titrated according to a predefined titration algorithm with a maximum dose of 50 dose steps (50 units IDeg/1.8 mg liraglutide). Adjustment of the dose was performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days. Adjustments were made in increments or decrements of 2 dose steps, aiming at a fasting glycaemic target of 4.0-5.0 mmol/L (71-90 mg/dL). That is, the adjustments were +2 or -2 if the mean of 3 pre-breakfast SMPG values were \>5.0 mmol/L (or \>90 mg/dL) and \<4.0 mmol/L (or \<71 mg/dL) respectively. No adjustment was done when the mean of 3 pre-breakfast SMPG values were 4.0 - 5.0 mmol/L (or 71-90 mg/dL). The subjects continued with pre-trial doses of metformin, unless there was a safety concern. | 278 |
| Insulin Glargine (IGlar) Eligible subjects received IGlar OD subcutaneously for a duration of 26 weeks. The treatment started with dose equal to the pre-trial daily dose (dose-to-dose switch), after which the dose was titrated according to the specified titration algorithm aiming at a fasting glycaemic target of 4.0-5.0 mmol/L (71-90 mg/dL). No predefined maximum dose was specified for IGlar. The subjects continued with pre-trial doses of metformin, unless there was a safety concern. | 279 |
| Total | 557 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Unclassified | 1 | 1 |
| Overall Study | Withdrawal Criteria | 16 | 11 |
Baseline characteristics
| Characteristic | Insulin Degludec/Liraglutide (IDegLira) | Insulin Glargine (IGlar) | Total |
|---|---|---|---|
| Age, Continuous | 58.4 Years STANDARD_DEVIATION 9.8 | 59.1 Years STANDARD_DEVIATION 9.3 | 58.8 Years STANDARD_DEVIATION 9.5 |
| Body weight | 88.3 Kg STANDARD_DEVIATION 17.5 | 87.3 Kg STANDARD_DEVIATION 15.8 | 87.8 Kg STANDARD_DEVIATION 16.6 |
| Glycated hemoglobin (HbA1c) | 8.4 Percentage (%) STANDARD_DEVIATION 0.9 | 8.2 Percentage (%) STANDARD_DEVIATION 0.9 | 8.3 Percentage (%) STANDARD_DEVIATION 0.9 |
| Sex: Female, Male Female | 135 Participants | 142 Participants | 277 Participants |
| Sex: Female, Male Male | 143 Participants | 137 Participants | 280 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 52 / 278 | 22 / 279 |
| serious Total, serious adverse events | 5 / 278 | 9 / 279 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Change from baseline in HbA1c after 26 weeks of treatment
Time frame: Week 0, week 26
Population: FAS was used for analysis of this endpoint. And FAS included all randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide (IDegLira) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -1.81 Percentage (%) | Standard Deviation 1.08 |
| Insulin Glargine (IGlar) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -1.13 Percentage (%) | Standard Deviation 0.98 |
Comparison: This primary endpoint was analysed on the FAS using an ANCOVA model with treatment and region as fixed effects and baseline HbA1c value as covariate.p-value: <0.00195% CI: [-0.74, -0.45]ANCOVA
Secondary
Change From Baseline in Body Weight
Change from baseline in body weight after 26 weeks of treatment
Time frame: Week 0, week 26
Population: FAS which included all randomised subjects was used for analysis of this endpoint. Missing values (including intermittent missing values) were imputed using LOCF method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide (IDegLira) | Change From Baseline in Body Weight | -1.4 Kg | Standard Deviation 3.5 |
| Insulin Glargine (IGlar) | Change From Baseline in Body Weight | 1.8 Kg | Standard Deviation 3.6 |
Secondary
Number of Treatment Emergent Confirmed Hypoglycaemic Episodes
Confirmed hypoglycaemic episodes were defined as either: Severe (i.e., an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) or an episode biochemically confirmed by a plasma glucose value of \<3.1 mmol/L (56 mg/dL), with or without symptoms consistent with hypoglycaemia.
Time frame: During 26 weeks of treatment
Population: The safety analysis set was used for analysis of this endpoint and this set included all subjects receiving at least one dose of trial product. Subjects contributed to the evaluation as treated. Confirmed hypoglycaemic episodes were reported by 79 subjects in IdegLira arm and by 137 subjects in IGlar arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide (IDegLira) | Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | 289 Number of episodes |
| Insulin Glargine (IGlar) | Number of Treatment Emergent Confirmed Hypoglycaemic Episodes | 683 Number of episodes |