Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted globally. The aim of this trial is to compare efficacy and safety of insulin degludec/liraglutide (IDegLira) versus basal-bolus therapy in combination with metformin in subjects with type 2 diabetes mellitus.
Interventions
DRUGinsulin degludec/liraglutide
Once daily injected s.c./subcutaneously (under the skin) in combination with metformin.
DRUGinsulin glargine
Once daily injected s.c./subcutaneously (under the skin) in combination with metformin.
DRUGinsulin aspart
Injected s.c./subcutaneously (under the skin) before each main meal.
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
* Male or female, age at least 18 years at the time of signing informed consent * Type 2 diabetes subjects (diagnosed clinically) at least 6 months prior to screening * HbA1c (glycosylated haemoglobin) 7.0-10.0% \[53mmol/mol-86mmol/mol\] (both inclusive) by central laboratory analysis * Current treatment with IGlar (insulin glargine) for at least 90 calendar days prior to screening * Stable daily dose of IGlar between 20 units and 50 units (both inclusive) for at least 56 calendar days prior to screening. Individual fluctuations of plus/minus 10% within the 56 calendar days prior to screening are acceptable, however on the day of screening total daily dose should be within the range of 20 units-50 units both inclusive * Stable daily dose of metformin (at least 1500 mg or max tolerated dose) for at least 90 calendar days prior to screening * Body mass index (BMI) below or equal to 40 kg/m\^2
Exclusion criteria
* Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 90 calendar days before screening * Anticipated initiation or change in concomitant medications in excess of 14 calendar days known to affect weight or glucose metabolism, such as weight loss/modifying (e.g.; sibutramine, orlistat, thyroid hormones, corticosteroids) * Impaired liver function, defined as alanine aminotransferase (ALT) at least 2.5 times upper limit of normal * Renal impairment eGFR (electronic case report form) below 60 mL/min/1.73 m\^2 as per CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) * Screening calcitonin at least 50 ng/L * History of pancreatitis (acute or chronic) * Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (Glycosylated Haemoglobin) | Week 0, Week 26 | Change in HbA1c values after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemic Episodes. | Weeks 0-26 | Severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe and/or BG confirmed by a plasma glucose value of \<56 mg/dL (3.1 mmol/L), with symptoms consistent with hypoglycaemia. |
| Change in Body Weight | Week 0, Week 26 | Change in body weight after 26 weeks of treatment. |
| Responder for HbA1c Below 7.0% | After 26 weeks of treatment | Number of subjects with HbA1c below 7% after 26 weeks of treatment. |
| Responder for HbA1c Below or Equal to 6.5 % | After 26 weeks of treatment | Number of subjects with HbA1c below 6.5% after 26 weeks of treatment. |
Countries
Argentina, Czechia, France, Greece, Hungary, Israel, Mexico, Russia, Slovakia, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
The trial was conducted at 89 sites in 12 countries: Argentina (3 sites), Czech Republic (5 sites), France (3 sites), Greece (6 sites), Hungary (3 sites), Israel (6 sites), Mexico (3 sites), Russia (7 sites), Slovakia (5 sites), Spain (6 sites), Turkey (5 sites) and United States (37 sites).
Pre-assignment details
Subjects with type 2 diabetes mellitus were on treatment with stable daily dose of insulin glargine (IGlar) 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 maximum tolerated dose) for at least 90 days prior to screening.
Participants by arm
| Arm | Count |
|---|---|
| IDegLira Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously once daily (OD) for a duration of 26 weeks. IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L \[72- 90 mg/dL\]).The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern. | 252 |
| IGlar + IAsp Subjects received insulin glargine plus prandial insulin aspart subcutaneously for duration of 26 weeks. A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®) was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L \[72- 90 mg/dL\]). The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 - 6.0 mmol/L). | 254 |
| Total | 506 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Unclassified | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | IDegLira | IGlar + IAsp | Total |
|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 9 | 58.0 years STANDARD_DEVIATION 8.6 | 58.3 years STANDARD_DEVIATION 8.8 |
| Body Weight | 87.2 kg STANDARD_DEVIATION 16 | 88.2 kg STANDARD_DEVIATION 17.2 | 87.7 kg STANDARD_DEVIATION 16.6 |
| Glycosylated haemoglobin (HbA1c) | 8.21 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.76 | 8.24 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.81 | 8.22 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.78 |
| Sex: Female, Male Female | 142 Participants | 137 Participants | 279 Participants |
| Sex: Female, Male Male | 110 Participants | 117 Participants | 227 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 84 / 252 | 79 / 253 |
| serious Total, serious adverse events | 12 / 252 | 10 / 253 |
Outcome results
Primary
Change in HbA1c (Glycosylated Haemoglobin)
Change in HbA1c values after 26 weeks of treatment.
Time frame: Week 0, Week 26
Population: The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation as randomised. 8 subjects in IDegLira and 9 subjects in IGlar + IAsp arm did not contribute to the analysis for this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| IDegLira | Change in HbA1c (Glycosylated Haemoglobin) | -1.48 Percentage of glycosylated haemoglobin | Standard Error 0.05 |
| IGlar + IAsp | Change in HbA1c (Glycosylated Haemoglobin) | -1.46 Percentage of glycosylated haemoglobin | Standard Error 0.05 |
Comparison: Change from baseline in HbA1c was analysed using a mixed model for repeated measurements with an unstructured covariance matrix. The model included treatment, visit and region as fixed factors and baseline HbA1c as covariate. Interactions between visit and all factors and the covariate were also included in the model.p-value: <0.000195% CI: [-0.16, 0.12]Mixed Models Analysis
Secondary
Change in Body Weight
Change in body weight after 26 weeks of treatment.
Time frame: Week 0, Week 26
Population: The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation as randomised. 08 subjects in both IDegLira and IGlar + IAsp arm did not contribute to the analysis for this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| IDegLira | Change in Body Weight | -0.93 kg | Standard Error 0.22 |
| IGlar + IAsp | Change in Body Weight | 2.64 kg | Standard Error 0.22 |
Comparison: Body weight measurements were analysed using a linear mixed model with an unstructured covariance matrix. The model included treatment, visit and region as fixed factors and baseline bodyweight as covariate. Interactions between visit and all factors and the covariate were also included in the model. The test for superiority of the confirmatory secondary endpoints was carried out only if non-inferiority of IDegLira vs basal-bolus for primary endpoint was confirmed.p-value: <0.000195% CI: [-4.19, -2.95]Mixed Models Analysis
Secondary
Number of Treatment Emergent Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemic Episodes.
Severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe and/or BG confirmed by a plasma glucose value of \<56 mg/dL (3.1 mmol/L), with symptoms consistent with hypoglycaemia.
Time frame: Weeks 0-26
Population: The safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product or comparator. Subjects in the safety set contributed to the evaluation as treated. One subject in IGlar + IAsp arm did not contribute to the analysis for this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegLira | Number of Treatment Emergent Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemic Episodes. | 129 Number of episodes |
| IGlar + IAsp | Number of Treatment Emergent Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemic Episodes. | 975 Number of episodes |
Comparison: Hypoglycaemic episodes were analysed using a negative binomial regression. The model included treatment and region as fixed factors and logarithm of the time period in which a hypoglycaemic episode considered treatment emergent as offset. The test for superiority of the confirmatory secondary endpoints was carried out only if non-inferiority of IDegLira vs basal-bolus for primary endpoint was confirmed.p-value: <0.000195% CI: [0.08, 0.17]Negative binomial regression model
Secondary
Responder for HbA1c Below 7.0%
Number of subjects with HbA1c below 7% after 26 weeks of treatment.
Time frame: After 26 weeks of treatment
Population: The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation as randomised. 14 subjects in IDegLira and 21 subjects in IGlar + IAsp arm did not contribute to the analysis for this endpoint.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IDegLira | Responder for HbA1c Below 7.0% | Yes | 157 Participants |
| IDegLira | Responder for HbA1c Below 7.0% | No | 81 Participants |
| IGlar + IAsp | Responder for HbA1c Below 7.0% | Yes | 156 Participants |
| IGlar + IAsp | Responder for HbA1c Below 7.0% | No | 77 Participants |
Secondary
Responder for HbA1c Below or Equal to 6.5 %
Number of subjects with HbA1c below 6.5% after 26 weeks of treatment.
Time frame: After 26 weeks of treatment
Population: The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation as randomised. 14 subjects in IDegLira and 21 subjects in IGlar + IAsp arm did not contribute to the analysis for this endpoint.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IDegLira | Responder for HbA1c Below or Equal to 6.5 % | Yes | 118 Participants |
| IDegLira | Responder for HbA1c Below or Equal to 6.5 % | No | 120 Participants |
| IGlar + IAsp | Responder for HbA1c Below or Equal to 6.5 % | Yes | 104 Participants |
| IGlar + IAsp | Responder for HbA1c Below or Equal to 6.5 % | No | 129 Participants |