Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted in Europe and 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), both with insulin aspart (IAsp) as mealtime insulin in subjects with type 1 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.
DRUGinsulin aspart
Administered 2-4 times 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
- Subjects fulfilling at least one of the below criteria: a) Experienced at least one severe hypo episode within the 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) c) Hypoglycaemic symptom unawareness d) Diabetes mellitus duration for more than 15 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) - Male or female, age at least 18 years at the time of signing informed consent - Type 1 diabetes mellitus (diagnosed clinically) for at least 52 weeks prior to Visit 1 - Current treatment with a basal-bolus regimen consisting of neutral protamine Hagedorn (NPH) insulin OD (once daily) / BID (twice daily) or insulin detemir (IDet) OD / BID plus 2-4 daily injections of any rapid acting meal time insulin or CSII (with rapid acting insulin) for at least 26 weeks prior to Visit 1 - HbA1c (glycosylated haemoglobin) below or equal to 10% by central laboratory analysis - BMI (body mass index) below or equal to 45 kg/m\^2
Exclusion criteria
- Treatment with IGlar or IDeg within the last 26 weeks prior to Visit 1 (short term use \[less than or equal to 2 weeks\] is allowed, but not within 4 weeks prior to screening) - Use of any other anti-diabetic agent 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 (Blood Glucose) Confirmed Symptomatic Hypoglycaemic Episodes During the Maintenance Period | A 16-week treatment 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 \<3.1 mmol/L (56 mg/dL), 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. Maintenance period: 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Severe or BG Confirmed Symptomatic Nocturnal Hypoglycaemic Episodes 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 \<3.1 mmol/L (56 mg/dL), 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 absolute value was considered as baseline for calculating change from baseline in HbA1c at week 64. |
| FPG (Fasting Plasma Glucose) | Week 32 and Week 64 | Fasting plasma glucose values at week 32 and week 64. |
Countries
Poland, Puerto Rico, United States
Participant flow
Recruitment details
The trial was conducted at 90 sites in 2 countries, as follows: US: 84 sites, Poland: 6 sites.
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 s.c.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 OD at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IDeg and IGlar were reduced by 20% at the start of both the treatment periods. Doses of IDeg and IGlar were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast SMPG values measured on 3 consecutive days immediately prior to titration fasting glycaemic target of 4.0-5.0 mmol/L). | 249 |
| 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 s.c. 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 OD at the same time of day throughout the trial. To prevent an increased risk of hypoglycaemia in the first treatment month, the overall daily doses of IGlar and IDeg were reduced by 20% at the start of both the treatment periods. Doses of IGlar and IDeg were titrated individually. Titration of the dose was performed once weekly based on the lowest of 3 pre-breakfast SMPG values measured on 3 consecutive days immediately prior to titration (fasting glycaemic target of 4.0-5.0 mmol/L). | 252 |
| Total | 501 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 10 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 6 | 7 |
| Overall Study | Pregnancy | 0 | 3 |
| Overall Study | Protocol Violation | 7 | 10 |
| Overall Study | Unclassified | 0 | 1 |
| Overall Study | Withdrawal by Subject | 25 | 25 |
Baseline characteristics
| Characteristic | Insulin Degludec/Insulin Glargine (IDeg/IGlar) | Insulin Glargine/Insulin Degludec (IGlar/IDeg) | Total |
|---|---|---|---|
| Age, Continuous | 45.4 years STANDARD_DEVIATION 13.7 | 46.4 years STANDARD_DEVIATION 14.6 | 45.9 years STANDARD_DEVIATION 14.2 |
| Fasting plasma glucose (FPG) | 165.1 mg/dL STANDARD_DEVIATION 77.3 | 174.4 mg/dL STANDARD_DEVIATION 81.7 | 169.8 mg/dL STANDARD_DEVIATION 79.6 |
| Glycosylated hemoglobin (HbA1c) | 7.7 Percentage of HbA1c STANDARD_DEVIATION 1 | 7.5 Percentage of HbA1c STANDARD_DEVIATION 1 | 7.6 Percentage of HbA1c STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 123 Participants | 109 Participants | 232 Participants |
| Sex: Female, Male Male | 126 Participants | 143 Participants | 269 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 97 / 454 | 97 / 460 |
| serious Total, serious adverse events | 58 / 454 | 70 / 460 |
Outcome results
Primary
Number of Treatment Emergent Severe or BG (Blood Glucose) 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 \<3.1 mmol/L (56 mg/dL), 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. Maintenance period: 16 weeks of treatment, in each treatment period (Week 16-32 and Week 48-64).
Time frame: A 16-week treatment period.
Population: The trial followed a cross over design. Descriptive analysis was based on the safety analysis set (SAS: subjects receiving at least 1 dose of the investigational product, IDeg or its comparator, IGlar). Number of subjects analysed=subjects in the SAS, who were exposed in at least one maintenance period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec (IDeg) | Number of Treatment Emergent Severe or BG (Blood Glucose) Confirmed Symptomatic Hypoglycaemic Episodes During the Maintenance Period | 2772 Event |
| Insulin Glargine (IGlar) | Number of Treatment Emergent Severe or BG (Blood Glucose) Confirmed Symptomatic Hypoglycaemic Episodes During the Maintenance Period | 3126 Event |
Comparison: Statistical analysis was performed on the FAS. Number of subjects analysed=subjects in the FAS, who were exposed in at least one maintenance period. Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 1: Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the maintenance period.p-value: <0.000195% CI: [0.85, 0.94]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 absolute value was considered as baseline for calculating change from baseline in HbA1c at week 64.
Time frame: Week 32, Week 64
Population: Both descriptive analysis and statistical analysis were based on the FAS. Here, 'n' specifies the number of subjects with available data at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec (IDeg) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | week 32 (n=209, 205) | -0.73 Percentage of glycosylated haemoglobin | Standard Deviation 0.89 |
| Insulin Degludec (IDeg) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | week 64 (n=203, 199) | 0.04 Percentage of glycosylated haemoglobin | Standard Deviation 0.51 |
| Insulin Glargine (IGlar) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | week 32 (n=209, 205) | -0.66 Percentage of glycosylated haemoglobin | Standard Deviation 0.76 |
| Insulin Glargine (IGlar) | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | week 64 (n=203, 199) | 0.17 Percentage of glycosylated haemoglobin | Standard Deviation 0.64 |
Comparison: Change from baseline in HbA1c at week 32 (treatment period 1). Before testing the primary endpoint, the secondary supportive efficacy endpoint Change from baseline in HbA1c after 32 weeks of treatment was tested for non-inferiority as a prerequisite for testing the primary endpoint. Analysis was based on mixed model for repeated measurement (MMRM); treatment, sex, region, pre-trial insulin treatment regimen, visit and dosing time were fixed effects, and age and baseline HbA1c were covariates.95% CI: [-0.1, 0.15]
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 based on MMRM; treatment, sex, region, pre-trial insulin treatment regimen, visit and dosing time were fixed effects, and age and baseline HbA1c were covariates95% CI: [0, 0.23]
Secondary
FPG (Fasting Plasma Glucose)
Fasting plasma glucose values at week 32 and week 64.
Time frame: Week 32 and Week 64
Population: Results are based on the FAS. Here, 'n' specifies the number of subjects with available data at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec (IDeg) | FPG (Fasting Plasma Glucose) | week 32 (n=208, 204) | 7.45 mmol/L | Standard Deviation 3.57 |
| Insulin Degludec (IDeg) | FPG (Fasting Plasma Glucose) | week 64 (n=203, 201) | 8.62 mmol/L | Standard Deviation 4.24 |
| Insulin Glargine (IGlar) | FPG (Fasting Plasma Glucose) | week 32 (n=208, 204) | 8.12 mmol/L | Standard Deviation 3.56 |
| Insulin Glargine (IGlar) | FPG (Fasting Plasma Glucose) | week 64 (n=203, 201) | 7.54 mmol/L | Standard Deviation 3.68 |
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: The trial followed a cross over design. Results are based on the SAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec (IDeg) | Incidence of Treatment Emergent Adverse Events | 925 Event |
| Insulin Glargine (IGlar) | Incidence of Treatment Emergent Adverse Events | 937 Event |
Secondary
Number of Treatment Emergent Severe or BG Confirmed Symptomatic Nocturnal Hypoglycaemic Episodes 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 \<3.1 mmol/L (56 mg/dL), 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 SAS. Number of subjects analysed=subjects in the SAS, who were exposed in at least one maintenance period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec (IDeg) | Number of Treatment Emergent Severe or BG Confirmed Symptomatic Nocturnal Hypoglycaemic Episodes During the Maintenance Period | 349 Event |
| Insulin Glargine (IGlar) | Number of Treatment Emergent Severe or BG Confirmed Symptomatic Nocturnal Hypoglycaemic Episodes During the Maintenance Period | 544 Event |
Comparison: Statistical analysis was performed on the FAS. Number of subjects analysed=subjects in the FAS, who were exposed in at least one maintenance period. 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: [0.56, 0.73]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 SAS. Number of subjects analysed=subjects in the SAS, who were exposed in at least one maintenance period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec (IDeg) | Proportion of Subjects With One or More Severe Hypoglycaemic Episodes During the Maintenance Period | 10.3 Percentage of subjects |
| Insulin Glargine (IGlar) | Proportion of Subjects With One or More Severe Hypoglycaemic Episodes During the Maintenance Period | 17.1 Percentage of subjects |
Comparison: Statistical analysis was performed on the FAS. Number of subjects analysed=subjects in the FAS, who were exposed in both the maintenance periods. Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 3: Proportion of subjects with one or more severe hypoglycaemic episodes during the maintenance period.p-value: 0.0016McNemar