Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in the United States of America (USA). The aim of the trial is to compare the safety and efficacy of insulin degludec (IDeg) and insulin glargine (IGlar) with or without OADs (oral anti-diabetic drugs) excluding SUs (sulfonylureas)/glinides in subjects with type 2 diabetes.
Interventions
DRUGinsulin degludec
Administered once daily injected s.c. / subcutaneously (under the skin). Dose is individually adjusted.
DRUGinsulin glargine
Administered once daily injected s.c. / subcutaneously (under the skin). Dose is individually adjusted.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
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 - Subjects fulfilling at least one of the below criteria: a) Experienced at least one severe hypoglycaemic episode within last year (according to the ADA (American Diabetes Association) definition, April 2013), b) Moderate chronic renal failure, defined as glomerular filtration rate 30 - 59 mL/min/1.73 m\^2 per CKD-Epi (Chronic Kidney Disease Epidemiology Collaboration) by central laboratory analysis, c) Hypoglycaemic symptom unawareness, d) Exposed to insulin for more than 5 years, e) Recent episode of hypoglycaemia (defined by symptoms of hypoglycaemia and/or episode with low glucose measurement (below or equal to 70 mg/dL \[below or equal to 3.9 mmol/L\])) within the last 12 weeks prior to Visit 1 (screening) - Type 2 diabetes mellitus (diagnosed clinically) for at least 26 weeks prior to Visit 1 - Current treatment with any basal insulin (OD or BID) ± any combination of OADs (metformin, DPP-4 inhibitor, alpha-glucosidase inhibitor, thiazolidinediones, and SGLT2-inhibitor) for 26 weeks or longer prior to Visit 1 For subjects on BID the total daily dose should be below 75 units - HbA1c (glycosylated haemoglobin) below or equal to 9.5 % by central laboratory analysis - BMI (body mass index) below or equal to 45 kg/m\^2
Exclusion criteria
- Treatment with a bolus insulin separately or contained in an insulin mix product within the last 26 weeks prior to Visit 1 - Use of any other anti-diabetic agent(s) than those stated in the inclusion criteria within the last 26 weeks prior to Visit 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Maintenance Period | After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64) | 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. Treatment emergent hypoglycaemic episode was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Severe or BG Confirmed Symptomatic Nocturnal Hypoglycaemic Episode During the Maintenance Period | After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64) | Severe or BG confirmed symptomatic nocturnal 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 and with time of onset between 00:01 and 05.59 a.m., both inclusive. Treatment emergent hypoglycaemic episode was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. |
| Proportion of Subjects With One or More Severe Hypoglycaemic Episodes During the Maintenance Period | After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64) | Percentage of subjects who experienced one or more severe hypoglycaemic episodes during the maintenance period. Severe hypoglycaemia (according to the American Diabetes Association 2013 definition): A hypoglycaemic episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose values may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. |
| Incidence of Treatment Emergent Adverse Events | During 32 weeks of treatment for each treatment period | Treatment emergent adverse event was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. |
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 32, Week 64 | Change from baseline in HbA1c (glycosylated haemoglobin) at week 32 (treatment period 1) and at week 64 (treatment period 2). Week 32 HbA1c value was considered as baseline for calculating change from baseline in HbA1c at week 64. |
| FPG (Fasting Plasma Glucose) | week 32, week 64 | Fasting plasma glucose values at week 32 and week 64. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
The trial was conducted at 152 sites in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Degludec/Insulin Glargine (IDeg/IGlar) Subjects received IDeg in treatment period 1 and IGlar in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IDeg and IGlar were administered in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and were to be taken at the same time of day throughout the trial. Subjects receiving pre-trial once daily basal insulin were to continue on their pre-trial basal insulin dose. For subjects receiving pre-trial twice daily basal insulin, a 20% reduction of the total daily insulin dose was recommended. Doses of IDeg and IGlar were titrated individually. Adjustment of the dose was performed once weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days (fasting glycaemic target of 4.0-5.0 mmol/L). | 360 |
| Insulin Glargine/Insulin Degludec (IGlar/IDeg) Subjects received IGlar in treatment period 1 and IDeg in treatment period 2. Each treatment period consisted of a 16-week titration period and a 16-week maintenance period (total 32 weeks for each treatment period). IGlar and IDeg were administered in the morning (from waking up to breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and were to be taken at the same time of day throughout the trial. Subjects receiving pre-trial once daily basal insulin were to continue on their pre-trial basal insulin dose. For subjects receiving pre-trial twice daily basal insulin, a 20% reduction of the total insulin daily dose was recommended. Doses of IGlar and IDeg were titrated individually. Adjustment of the dose was performed once weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days (fasting glycaemic target of 4.0-5.0 mmol/L). | 360 |
| Total | 720 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 | Adverse Event | 5 | 7 |
| Treatment Period 1 | Casebook Unsigned | 1 | 0 |
| Treatment Period 1 | Lack of Efficacy | 0 | 1 |
| Treatment Period 1 | Lost to Follow-up | 11 | 3 |
| Treatment Period 1 | Protocol Violation | 22 | 17 |
| Treatment Period 1 | Unclassified | 1 | 0 |
| Treatment Period 1 | Withdrawal by Subject | 13 | 17 |
| Treatment Period 2 | Adverse Event | 4 | 4 |
| Treatment Period 2 | Lack of Efficacy | 2 | 1 |
| Treatment Period 2 | Lost to Follow-up | 4 | 2 |
| Treatment Period 2 | Protocol Violation | 1 | 2 |
| Treatment Period 2 | Unclassified | 1 | 0 |
| Treatment Period 2 | Withdrawal by Subject | 13 | 9 |
Baseline characteristics
| Characteristic | Insulin Degludec/Insulin Glargine (IDeg/IGlar) | Insulin Glargine/Insulin Degludec (IGlar/IDeg) | Total |
|---|---|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 10.7 | 61.2 years STANDARD_DEVIATION 10.3 | 61.4 years STANDARD_DEVIATION 10.5 |
| Fasting plasma glucose | 139.2 mg/dL STANDARD_DEVIATION 53.5 | 134.9 mg/dL STANDARD_DEVIATION 51.6 | 137.0 mg/dL STANDARD_DEVIATION 52.6 |
| Glycosylated haemoglobin | 7.6 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.1 | 7.6 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.1 | 7.6 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.1 |
| Sex: Female, Male Female | 169 Participants | 169 Participants | 338 Participants |
| Sex: Female, Male Male | 191 Participants | 191 Participants | 382 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 93 / 671 | 77 / 665 |
| serious Total, serious adverse events | 64 / 671 | 65 / 665 |
Outcome results
Primary
Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Maintenance Period
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. Treatment emergent hypoglycaemic episode was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment.
Time frame: After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64)
Population: The trial followed a cross over design. Descriptive analysis was based on the safety analysis set (subjects receiving at least one dose of the investigational product or its comparator). Number of subjects analysed=subjects with available data for the endpoint as per individual trial products. Statistical analysis was performed on full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec (IDeg) | Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Maintenance Period | 353 events |
| Insulin Glargine (IGlar) | Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Maintenance Period | 496 events |
Comparison: Stepwise hierarchical testing procedure was applied for confirmatory endpoints:~Step 1: Primary analysis: Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the maintenance periodp-value: <0.000195% CI: [0.61, 0.8]Poisson
Secondary
Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Change from baseline in HbA1c (glycosylated haemoglobin) at week 32 (treatment period 1) and at week 64 (treatment period 2). Week 32 HbA1c value was considered as baseline for calculating change from baseline in HbA1c at week 64.
Time frame: Week 32, Week 64
Population: Full analysis set. Here, 'n' specifies the number of subjects with available data at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec (IDeg) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | week 32 (n=308, 313) | -0.49 percentage of glycosylated haemoglobin | Standard Deviation 0.99 |
| Insulin Degludec (IDeg) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | week 64 (n=295, 301) | 0.03 percentage of glycosylated haemoglobin | Standard Deviation 0.75 |
| Insulin Glargine (IGlar) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | week 32 (n=308, 313) | -0.58 percentage of glycosylated haemoglobin | Standard Deviation 1.02 |
| Insulin Glargine (IGlar) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | week 64 (n=295, 301) | 0.10 percentage of glycosylated haemoglobin | Standard Deviation 0.83 |
Comparison: Change from baseline in HbA1c at week 32 (treatment period 1). Before the primary endpoint was tested, the secondary supportive efficacy endpoint Change from baseline in HbA1c after 32 weeks of treatment was tested for non-inferiority as prerequisite for testing the primary endpoint. Analysis was performed using a mixed model for repeated measurement (MMRM) with treatment, sex, antidiabetic therapy at screening, visit and dosing time as fixed effects, and age and baseline HbA1c as covariates.95% CI: [-0.04, 0.23]
Comparison: Change from baseline in HbA1c at week 64 (treatment period 2). The baseline values are week 32 values. Before the primary endpoint was tested, the secondary supportive efficacy endpoint Change from baseline in HbA1c after 32 weeks of treatment was tested for non-inferiority as prerequisite for testing the primary endpoint. Analysis was performed using a MMRM with treatment, sex, antidiabetic therapy at screening, visit and dosing time as fixed effects, and age and baseline HbA1c as covariates.95% CI: [-0.07, 0.18]
Secondary
FPG (Fasting Plasma Glucose)
Fasting plasma glucose values at week 32 and week 64.
Time frame: week 32, week 64
Population: Full analysis set. Here, 'n' specifies the number of subjects with available data at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec (IDeg) | FPG (Fasting Plasma Glucose) | week 32 (n=307, 311) | 107.33 mg/dL | Standard Deviation 41.72 |
| Insulin Degludec (IDeg) | FPG (Fasting Plasma Glucose) | week 64 (n=293, 302) | 114.07 mg/dL | Standard Deviation 51.91 |
| Insulin Glargine (IGlar) | FPG (Fasting Plasma Glucose) | week 32 (n=307, 311) | 106.96 mg/dL | Standard Deviation 39.81 |
| Insulin Glargine (IGlar) | FPG (Fasting Plasma Glucose) | week 64 (n=293, 302) | 107.55 mg/dL | Standard Deviation 51.3 |
Secondary
Incidence of Treatment Emergent Adverse Events
Treatment emergent adverse event was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment.
Time frame: During 32 weeks of treatment for each treatment period
Population: Safety analysis set included all subjects receiving at least one dose of the investigational product or its comparator (Total number of subjects analysed for this endpoint: 713).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec (IDeg) | Incidence of Treatment Emergent Adverse Events | 1293 events |
| Insulin Glargine (IGlar) | Incidence of Treatment Emergent Adverse Events | 1381 events |
Secondary
Number of Treatment Emergent Severe or BG Confirmed Symptomatic Nocturnal Hypoglycaemic Episode During the Maintenance Period
Severe or BG confirmed symptomatic nocturnal 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 and with time of onset between 00:01 and 05.59 a.m., both inclusive. Treatment emergent hypoglycaemic episode was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment.
Time frame: After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64)
Population: The trial followed a cross over design. Descriptive analysis was based on the safety analysis set (subjects receiving at least one dose of the investigational product or its comparator). Number of subjects analysed=subjects with available data for the endpoint as per individual trial products. Statistical analysis was performed on full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec (IDeg) | Number of Treatment Emergent Severe or BG Confirmed Symptomatic Nocturnal Hypoglycaemic Episode During the Maintenance Period | 105 events |
| Insulin Glargine (IGlar) | Number of Treatment Emergent Severe or BG Confirmed Symptomatic Nocturnal Hypoglycaemic Episode During the Maintenance Period | 175 events |
Comparison: Stepwise hierarchical testing procedure was applied for confirmatory endpoints:~Step 2: Number of treatment-emergent severe or BG confirmed symptomatic nocturnal hypoglycaemic episodes during the maintenance period.p-value: <0.000195% CI: [0.46, 0.74]Poisson
Secondary
Proportion of Subjects With One or More Severe Hypoglycaemic Episodes During the Maintenance Period
Percentage of subjects who experienced one or more severe hypoglycaemic episodes during the maintenance period. Severe hypoglycaemia (according to the American Diabetes Association 2013 definition): A hypoglycaemic episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose values may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.
Time frame: After 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64)
Population: The trial followed a cross over design. Descriptive analysis was based on the safety analysis set. Number of subjects analysed=subjects with available data for the endpoint as per individual trial products. Statistical analysis was performed on subjects in full analysis set with exposure in both maintenance periods.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec (IDeg) | Proportion of Subjects With One or More Severe Hypoglycaemic Episodes During the Maintenance Period | 1.6 percentage of subjects |
| Insulin Glargine (IGlar) | Proportion of Subjects With One or More Severe Hypoglycaemic Episodes During the Maintenance Period | 2.4 percentage of subjects |
Comparison: Stepwise hierarchical testing procedure:~Step 3: Proportion of subjects with one or more severe hypoglycaemic episodes in the maintenance period.p-value: 0.3458McNemar