Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted globally. The aim of this trial is to compare the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin degludec (IDeg) and liraglutide (Lira) in subjects with type 2 diabetes. Subjects are to continue their pre-trial treatment with metformin or metformin + pioglitazone throughout the entire trial.
Interventions
DRUGinsulin degludec/liraglutide
Insulin degludec/liraglutide treatment will be initiated and titrated (individually adjusted) twice weekly according to the mean self measured plasma glucose (SMPG) (fasting). Insulin degludec/liraglutide is injected subcutaneously (under the skin) once daily.
DRUGinsulin degludec
Insulin degludec treatment will be initiated with 10 U and titrated (individually adjusted) twice weekly according to the mean SMPG (fasting). Insulin degludec is injected subcutaneously (under the skin) once daily.
DRUGliraglutide
Liraglutide will be started with 0.6 mg and subsequent 0.6 mg weekly dose escalation to 1.8 mg. Liraglutide dose of 1.8 mg/day will be continued for the remaining part of the trial. Liraglutide is injected subcutaneously (under the skin) once daily.
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
* Subjects with type 2 diabetes * HbA1c 7.0-10.0 % (both inclusive) with the aim of a median HbA1c of 8.3%. Accordingly, when approximately 50% of the randomised subjects have a HbA1c above 8.3%, the remaining subjects randomised must have a HbA1c of below or equal to 8.3%, or when approximately 50% of the randomised subjects have a HbA1c of below or equal to 8.3%, the remaining subjects randomised must have a HbA1c above 8.3% * Male or female, age 18 years or above (Taiwan: 20 years or above for a site 653 in Taiwan: Taichung Veterans General Hospital) * Subjects on stable dose of 1-2 OADs (metformin \[at least 1500 mg or max tolerated dose\] or metformin \[at least 1500 mg or max tolerated dose\] + pioglitazone \[at least 30 mg\]) for at least 90 days prior to screening * Body Mass Index (BMI) maximum 40 kg/m\^2
Exclusion criteria
* Treatment with insulin (except for short-term treatment due to intercurrent illness at the discretion of the Investigator) * Treatment with GLP-1 (glucagon-like peptide-1) receptor agonists (eg exenatide, liraglutide), sulphonylurea or dipeptidyl peptidase 4 (DPP-4) inhibitors within 90 days prior to trial * Impaired liver function, defined as alanine aminotransferese (ALAT) at least 2.5 times Upper Normal Range (UNR) (one retest analysed at the central laboratory within a week from first sample taken is permitted with the result of the last sample being the conclusive) * Impaired renal function defined as serum-creatinine at least 133 mcmol/l (at least 1.5 mg/dl) for males and at least 125 mcmol/l (at least 1.4) for females, or as allowed according to local contraindications for metformin (one retest analysed at the central laboratory within a week from first sample taken is permitted with the result of the last sample being the conclusive) * Screening calcitonin at least 50 ng/L * Subjects with personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN 2) * Cardiac disorder defined as: congestive heart failure (NYHA class III-IV), diagnosis of unstable angina pectoris, cerebral stroke and/or myocardial infarction within the last 12 months and planned coronary, carotid or peripheral artery revascularisation procedures * Severe uncontrolled treated or untreated hypertension (systolic blood pressure at least 180 mm Hg or diastolic blood pressure at least 100 mm Hg) * Acute treatment required proliferative retinopathy or maculopathy (macular oedema) * History of chronic pancreatitis or idiopathic acute pancreatitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 26. | Week 0, week 26 | Values of mean change in HbA1c. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Body Weight at Week 26 | Week 0, Week 26 | Values of mean change in body weight. |
| Number of Hypoglycaemic Episodes | Weeks 0-26 | Reported hypoglycemaic episodes are number of hypoglycemic events per 100 patient years of exposure. |
| Change From Baseline in Incremental Area Under the Curve 0-4h (iAUC0-4h) Derived From the Glucose Concentration Profile During Meal Test | Week 0, Week 26 | Values of mean change in normalised iAUC0-4h values based on LOCF data derived from the glucose concentration profiles during a meal test. The meal test was performed at selected sites at baseline and after 26 weeks of treatment in the main trial period. The incremental AUC was calculated using the trapezoidal method and the resulting area was divided length of the observation period to yield the (normalised) prandial increment in mmol/L using the available valid glucose observations and the associated actual elapsed time point. |
| Mean Actual Daily Insulin Dose | Week 26 | Mean of the actual doses recorded at visit 28 (Week 26). |
Countries
Australia, Canada, Finland, Germany, Hungary, India, Ireland, Italy, Malaysia, Mexico, Puerto Rico, Russia, Singapore, Slovakia, South Africa, Spain, Taiwan, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Countries: 19; Sites: 271; Number of sites as in parenthesis. Australia (7), Canada (14 ), Finland (5 ), Germany (12 ), Hungary (6), India (23), Ireland (2), Italy (6), Malaysia (5), Mexico (2 ), Russian Federation (11), Singapore (3), Slovakia (5), South Africa (13), Spain (8), Taiwan (3), Thailand (4), United Kingdom (16) and United States (126).
Pre-assignment details
Subjects on metformin and/or pioglitazone treatment underwent a 26-week main trial and continued to enter an additional 26-week extension trial. Total duration of the trial was up to 55 weeks (2 weeks screening + 26 week main period + 26 week extension period + 1 week follow-up after last dose).
Participants by arm
| Arm | Count |
|---|---|
| IDeg Insulin degludec (IDeg: 100 U/mL) was injected once daily (OD) subcutaneously (s.c.) for 26 weeks (main trial) + 26 weeks (extension trial). IDeg treatment was initiated at a dose of 10 units and titrated twice weekly to the fasting glycaemic target of 4.0-5.0 mmol/L (72-90 mg/dL) based on the mean fasting self-measured plasma glucose (SMPG) from 3 preceeding measurements. Pre-trial metformin/metformin + pioglitazone treatment was continued throughout the trial. | 413 |
| IDegLira Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously OD for 26 weeks(main trial) + 26 weeks (extension trial). IDegLira treatment was initiated at 10 dose steps (containing 10 units IDeg and 0.36 mg liraglutide) and titrated twice weekly to a fasting glycaemic target of 4.0-5.0 mmol/L (72-90 mg/dL) based on the mean SMPG (fasting) from 3 preceeding measurements. Pre-trial metformin/metformin + pioglitazone treatment was continued throughout the trial. | 833 |
| Liraglutide Liraglutide (6 mg/mL) was injected subcutaneously OD for 26 weeks (main trial). Liraglutide treatment was initiated at a dose of 0.6 mg/day, and subsequently increased by 0.6 mg in weekly dose escalation steps to reach maximum dose of 1.8 mg/day. Subjects continued with liraglutide 1.8 mg once daily in the 26 week extension period. Pre-trial metformin/metformin + pioglitazone treatment was continued throughout the trial. | 414 |
| Total | 1,660 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Week 0 to Week 26 | Adverse Event | 8 | 10 | 24 |
| Week 0 to Week 26 | Lack of Efficacy | 0 | 1 | 0 |
| Week 0 to Week 26 | Protocol Violation | 1 | 2 | 0 |
| Week 0 to Week 26 | Unclassified | 5 | 16 | 9 |
| Week 0 to Week 26 | Withdrawal Criteria | 34 | 69 | 40 |
| Week 27 to 52 | Adverse Event | 1 | 5 | 2 |
| Week 27 to 52 | Protocol Violation | 0 | 2 | 1 |
| Week 27 to 52 | Unclassified | 13 | 18 | 9 |
| Week 27 to 52 | Withdrawal Criteria | 14 | 19 | 16 |
Baseline characteristics
| Characteristic | IDeg | IDegLira | Liraglutide | Total |
|---|---|---|---|---|
| Age, Continuous | 54.9 years STANDARD_DEVIATION 9.7 | 55.1 years STANDARD_DEVIATION 9.9 | 55.0 years STANDARD_DEVIATION 10.2 | 55.0 years STANDARD_DEVIATION 9.9 |
| Body Weight | 87.4 kg STANDARD_DEVIATION 19.2 | 87.2 kg STANDARD_DEVIATION 19 | 87.4 kg STANDARD_DEVIATION 18 | 87.3 kg STANDARD_DEVIATION 18.8 |
| Glycosylated haemoglobin (HbA1c) | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 |
| Normalised Incremental Area under curve (AUC) | 4.12 mmol/L STANDARD_DEVIATION 1.8 | 4.11 mmol/L STANDARD_DEVIATION 2.05 | 4.12 mmol/L STANDARD_DEVIATION 1.82 | 4.11 mmol/L STANDARD_DEVIATION 1.93 |
| Sex: Female, Male Female | 213 Participants | 398 Participants | 206 Participants | 817 Participants |
| Sex: Female, Male Male | 200 Participants | 435 Participants | 208 Participants | 843 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 160 / 412 | 386 / 825 | 241 / 412 |
| serious Total, serious adverse events | 22 / 412 | 38 / 825 | 24 / 412 |
Outcome results
Primary
Mean Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 26.
Values of mean change in HbA1c.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects and missing data was imputed using LOCF. Three subjects did not have their case book signed off due to discontinuation of an investigator's participation in the trial; hence 1 subject from each arm was excluded from the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Mean Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 26. | -1.44 Percentage of glycosylated haemoglobin | Standard Deviation 1.03 |
| IDegLira | Mean Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 26. | -1.91 Percentage of glycosylated haemoglobin | Standard Deviation 1.07 |
| Liraglutide | Mean Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 26. | -1.28 Percentage of glycosylated haemoglobin | Standard Deviation 1.13 |
95% CI: [-0.58, -0.36]ANCOVA
95% CI: [-0.75, -0.53]ANCOVA
Secondary
Change From Baseline in Incremental Area Under the Curve 0-4h (iAUC0-4h) Derived From the Glucose Concentration Profile During Meal Test
Values of mean change in normalised iAUC0-4h values based on LOCF data derived from the glucose concentration profiles during a meal test. The meal test was performed at selected sites at baseline and after 26 weeks of treatment in the main trial period. The incremental AUC was calculated using the trapezoidal method and the resulting area was divided length of the observation period to yield the (normalised) prandial increment in mmol/L using the available valid glucose observations and the associated actual elapsed time point.
Time frame: Week 0, Week 26
Population: The number of subjects analysed were equal to study population in which the meal test was perfomed at selected sites. Missing data was imputed using LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Change From Baseline in Incremental Area Under the Curve 0-4h (iAUC0-4h) Derived From the Glucose Concentration Profile During Meal Test | -0.17 mmol/L | Standard Deviation 1.98 |
| IDegLira | Change From Baseline in Incremental Area Under the Curve 0-4h (iAUC0-4h) Derived From the Glucose Concentration Profile During Meal Test | -0.87 mmol/L | Standard Deviation 1.65 |
| Liraglutide | Change From Baseline in Incremental Area Under the Curve 0-4h (iAUC0-4h) Derived From the Glucose Concentration Profile During Meal Test | -0.78 mmol/L | Standard Deviation 1.62 |
Secondary
Mean Actual Daily Insulin Dose
Mean of the actual doses recorded at visit 28 (Week 26).
Time frame: Week 26
Population: The FAS included all randomised subjects. Missing data was imputed using LOCF. For 22 subjects, the dose values were missing hence did not contribute to the analysis. The comparison was made between the insulin products IDeg and IDeglira.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Mean Actual Daily Insulin Dose | 53 units | Standard Deviation 28 |
| IDegLira | Mean Actual Daily Insulin Dose | 38 units | Standard Deviation 13 |
Secondary
Mean Change From Baseline in Body Weight at Week 26
Values of mean change in body weight.
Time frame: Week 0, Week 26
Population: The FAS included all randomised subjects and missing data was imputed using LOCF. Three subjects did not have their case book signed off due to discontinuation of an investigator's participation in the trial; hence 1 subject from each arm was excluded from the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Mean Change From Baseline in Body Weight at Week 26 | 1.6 kg | Standard Deviation 4 |
| IDegLira | Mean Change From Baseline in Body Weight at Week 26 | -0.5 kg | Standard Deviation 3.5 |
| Liraglutide | Mean Change From Baseline in Body Weight at Week 26 | -3.0 kg | Standard Deviation 3.5 |
Secondary
Number of Hypoglycaemic Episodes
Reported hypoglycemaic episodes are number of hypoglycemic events per 100 patient years of exposure.
Time frame: Weeks 0-26
Population: The Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparators. The missing data was imputed using LOCF. The number of subjects analysed in SAS for each arm are 412, 825 and 412, respectively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg | Number of Hypoglycaemic Episodes | 256.7 Events per 100 patient years of exposure |
| IDegLira | Number of Hypoglycaemic Episodes | 180.2 Events per 100 patient years of exposure |
| Liraglutide | Number of Hypoglycaemic Episodes | 22.0 Events per 100 patient years of exposure |