Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted in Africa, Europe and the United States of America (USA). The aim of the trial is to compare NN1250 (insulin degludec, soluble insulin basal analogue (SIBA)) plus insulin aspart with insulin glargine (IGlar) plus insulin aspart in patients with type 1 diabetes. The main period is registered internally at Novo Nordisk as NN1250-3583 while the extension period is registered as NN1250-3644.
Interventions
DRUGinsulin degludec
Injected subcutaneously once daily. Dose was individually adjusted.
DRUGinsulin glargine
Injected subcutaneously once daily. Dose individually adjusted.
DRUGinsulin aspart
Injected subcutaneously as mealtime insulin. Dose was individually adjusted.
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 1 diabetes mellitus for at least 12 months * Current treatment with any basal bolus insulin for at least 12 months * HbA1c below or equal to 10.0% * BMI (Body Mass Index) below or equal to 35.0 kg/m\^2 * For the extension trial only: Completion of the 52 week treatment period in trial NN1250-3583 (NCT00982228)
Exclusion criteria
* Use of any other antidiabetic drug than insulin within the last 3 months * Cardiovascular disease within the last 6 months * Uncontrolled treated/untreated severe hypertension * Recurrent severe hypoglycemia or hypoglycemic unawareness or hospitalisation for diabetic ketoacidosis during the previous 6 months * Pregnancy, breast-feeding, the intention of becoming pregnant or not using adequate contraceptive measures according to local requirements * Cancer and medical history of cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | Week 0, Week 52 | Change from baseline in HbA1c after 52 weeks of treatment |
| Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Week 0 to Week 104 + 7 days follow up | Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. |
| Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | Week 0 to Week 104 + 7 days follow up | Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. |
| Extension Trial (Primary Endpoint): Cross-reacting Antibodies to Human Insulin | Week 0, Week 106 | The unit for measuring antibody levels is amount of tracer bound to the antibodies in the precipitate (B) expressed in percentage of the total amount of tracer (T) added to the mixture (%B/T). Samples were taken before 1st dosing and after a 1-week wash-out period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | Week 0 to Week 52 + 7 days follow up | Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occuring between 00:01 and 05:59 a.m. |
| Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | Week 0 to Week 104 + 7 days follow up | Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occuring between 00:01 and 05:59 a.m. |
| Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 52 | Week 52 | Mean of 9-point self-measured plasma glucose profile (SMPG) after 52 weeks of treatment. Plasma glucose measured: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, bedtime, at 4 am and before breakfast. |
| Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment | Week 0, Week 104 | Change from baseline in HbA1c after 104 weeks of treatment |
| Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 104 of Treatment | Treatment week 104 | Mean of 9-point self-measured plasma glucose profile (SMPG) after 104 weeks of treatment. Plasma glucose measured: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, bedtime, at 4 am and before breakfast. |
| Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | Week 0 to Week 52 + 7 days follow up | Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. |
Countries
France, Germany, Russia, South Africa, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 79 sites in 6 countries: France (6), Germany (5), Russia (7), South Africa (3), United Kingdom (U.K.) (6) and United States (U.S.) (52).
Pre-assignment details
All subjects who completed the 52-week main trial (NN1250-3583, NCT00982228) and were found to be eligible for the extension trial were offered to participate in the 52-week extension trial (NN1250-3644).
Participants by arm
| Arm | Count |
|---|---|
| IDeg OD Insulin degludec (IDeg) was given subcutaneously (s.c.) once daily (OD) in the evening in combination with insulin aspart (IAsp) as meal time insulin. IDeg was given for 52 weeks in the main period and for an additional 52 weeks in the extension period. | 472 |
| IGlar OD Insulin glargine (IGlar) was given s.c. once daily (OD) according to approved labelling in combination with insulin aspart (IAsp) as meal time insulin. IGlar was given for 52 weeks in the main period and for additional 52 weeks in the extension period. | 157 |
| Total | 629 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension: Week 53 to 104 (NN1250-3644) | Adverse Event | 3 | 2 |
| Extension: Week 53 to 104 (NN1250-3644) | Lack of Efficacy | 1 | 0 |
| Extension: Week 53 to 104 (NN1250-3644) | Protocol Violation | 1 | 2 |
| Extension: Week 53 to 104 (NN1250-3644) | Unclassified | 11 | 1 |
| Extension: Week 53 to 104 (NN1250-3644) | Withdrawal criteria | 5 | 0 |
| Main: Week 0 to 52 (NN1250-3583) | Adverse Event | 12 | 2 |
| Main: Week 0 to 52 (NN1250-3583) | Lack of Efficacy | 2 | 0 |
| Main: Week 0 to 52 (NN1250-3583) | Protocol Violation | 11 | 2 |
| Main: Week 0 to 52 (NN1250-3583) | Unclassified | 28 | 13 |
| Main: Week 0 to 52 (NN1250-3583) | Withdrawal criteria | 15 | 3 |
Baseline characteristics
| Characteristic | IDeg OD | IGlar OD | Total |
|---|---|---|---|
| Age, Continuous | 42.8 years STANDARD_DEVIATION 13.7 | 43.7 years STANDARD_DEVIATION 13.3 | 43.0 years STANDARD_DEVIATION 13.6 |
| Fasting plasma glucose (FPG) | 9.1 mmol/L STANDARD_DEVIATION 4 | 9.7 mmol/L STANDARD_DEVIATION 4.4 | 9.3 mmol/L STANDARD_DEVIATION 4.1 |
| Glycosylated haemoglobin (HbA1c) | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1 | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 194 Participants | 67 Participants | 261 Participants |
| Sex: Female, Male Male | 278 Participants | 90 Participants | 368 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 353 / 472 | 118 / 154 |
| serious Total, serious adverse events | 71 / 472 | 29 / 154 |
Outcome results
Primary
Extension Trial (Primary Endpoint): Cross-reacting Antibodies to Human Insulin
The unit for measuring antibody levels is amount of tracer bound to the antibodies in the precipitate (B) expressed in percentage of the total amount of tracer (T) added to the mixture (%B/T). Samples were taken before 1st dosing and after a 1-week wash-out period.
Time frame: Week 0, Week 106
Population: The SAS included all subjects who received at least one dose of the investigational product or its comparator in the main trial including subjects carried through to the extension trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Extension Trial (Primary Endpoint): Cross-reacting Antibodies to Human Insulin | 11.3 %B/T | Standard Deviation 15.6 |
| IGlar OD | Extension Trial (Primary Endpoint): Cross-reacting Antibodies to Human Insulin | 11.0 %B/T | Standard Deviation 16 |
Primary
Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes
Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L.
Time frame: Week 0 to Week 104 + 7 days follow up
Population: The SAS included all subjects who received at least one dose of the investigational product or its comparator in the main trial including subjects carried through to the extension trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 3750 Episodes/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 3743 Episodes/100 years of patient exposure |
Primary
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs)
Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect.
Time frame: Week 0 to Week 104 + 7 days follow up
Population: Safety analysis set (SAS) included all subjects who received at least one dose of the investigational product or its comparator in the main trial including subjects carried through to the extension trial.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AE) | 383 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 14 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 22 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 105 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 256 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Fatal AE | 1 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 242 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AE) | 374 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 106 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 17 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Fatal AE | 1 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 26 Events/100 years of patient exposure |
Primary
Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment
Change from baseline in HbA1c after 52 weeks of treatment
Time frame: Week 0, Week 52
Population: The full analysis set (FAS) included all randomised subjects and missing data was imputed using LOCF (last observation carried forward).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -0.40 percentage of glycosylated haemoglobin | Standard Deviation 0.73 |
| IGlar OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -0.39 percentage of glycosylated haemoglobin | Standard Deviation 0.84 |
Secondary
Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes
Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occuring between 00:01 and 05:59 a.m.
Time frame: Week 0 to Week 104 + 7 days follow up
Population: The SAS included all subjects who received at least one dose of the investigational product or its comparator in the main trial including subjects carried through to the extension trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 390 Episodes/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 532 Episodes/100 years of patient exposure |
Secondary
Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment
Change from baseline in HbA1c after 104 weeks of treatment
Time frame: Week 0, Week 104
Population: The FAS included all randomised subjects in the main trial including subjects carried through to the extension trial and missing data was imputed using LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment | -0.27 percentage of glycosylated haemoglobin | Standard Deviation 0.75 |
| IGlar OD | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment | -0.24 percentage of glycosylated haemoglobin | Standard Deviation 0.86 |
Secondary
Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 104 of Treatment
Mean of 9-point self-measured plasma glucose profile (SMPG) after 104 weeks of treatment. Plasma glucose measured: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, bedtime, at 4 am and before breakfast.
Time frame: Treatment week 104
Population: The FAS included all randomised subjects in the main trial including subjects carried through to the extension trial and missing data was imputed using LOCF. For 12 subjects all 9-point SMPG values were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 104 of Treatment | 8.0 mmol/L | Standard Deviation 2.2 |
| IGlar OD | Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 104 of Treatment | 8.1 mmol/L | Standard Deviation 2.2 |
Secondary
Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 52
Mean of 9-point self-measured plasma glucose profile (SMPG) after 52 weeks of treatment. Plasma glucose measured: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, bedtime, at 4 am and before breakfast.
Time frame: Week 52
Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 7 subjects all 9-point SMPG values were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 52 | 8.1 mmol/L | Standard Deviation 2.3 |
| IGlar OD | Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 52 | 8.3 mmol/L | Standard Deviation 2.4 |
Secondary
Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes
Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L.
Time frame: Week 0 to Week 52 + 7 days follow up
Population: The SAS included all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD | Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 4254 Episodes/100 years of patient exposure |
| IGlar OD | Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 4018 Episodes/100 years of patient exposure |
Secondary
Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes
Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occuring between 00:01 and 05:59 a.m.
Time frame: Week 0 to Week 52 + 7 days follow up
Population: The SAS included all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD | Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 441 Episodes/100 years of patient exposure |
| IGlar OD | Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 586 Episodes/100 years of patient exposure |