Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted in Asia, Europe, Japan and South America. The aim of the trial is to compare the efficacy, safety and tolerability of NN1250 (insulin degludec (\[Deg\]) with insulin detemir (IDet), both combined with insulin aspart. The main period is registered internally at Novo Nordisk as NN1250-3585 while the extension period is registered as NN1250-3725.
Interventions
DRUGinsulin degludec
Injected s.c. (under the skin) once daily. Dose was individually adjusted.
DRUGinsulin detemir
Injected s.c. (under the skin) once daily or twice daily (BID). Dose was individually adjusted.
DRUGinsulin aspart
Injected s.c. (under the skin) 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% * Body Mass Index (BMI) below or equal to 35.0 kg/m\^2 * For Japan only: Minimum age is 20 years * For the extension trial only: Completed the six-month treatment period in trial NN1250-3585 (NCT01074268)
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 * Cancer and medical history of cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | Week 0, Week 26 | Change from baseline in HbA1c after 26 weeks of treatment |
| Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Week 0 to Week 52 + 7 days follow up | Rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no/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 or important medical issues |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Extension 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) at week 52. Plasma glucose was measured before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before main evening meal, 90 minutes after the start of main evening meal, before bedtime, at 04:00 AM and before breakfast on the following day. |
| Main Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 26 Weeks of Treatment | Week 0, Week 26 | Change from baseline in FPG after 26 weeks of treatment |
| Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | Week 0, Week 52 | Change from baseline in FPG after 52 weeks of treatment |
| Extension Trial (Secondary 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 |
| Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | Week 0 to Week 26 + 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: episodes requiring active assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: episodes where subject was able to treat her/himself and plasma glucose below 3.1 mmol/L, with or without symptoms. Nocturnal hypoglycaemic episodes are defined as occuring between 00:01 and 05:59 a.m. |
| Extension 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: episodes requiring active assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: episodes where the subject was able to treat her/himself and plasma glucose below 3.1 mmol/L with or without symptoms |
| Extension 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: episodes requiring active assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: episodes where subject was able to treat her/himself and plasma glucose below 3.1 mmol/L, with or without symptoms. Nocturnal hypoglycaemic episodes are defined as occuring between 00:01 and 05:59 a.m. |
| Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | Week 0 to Week 26 + 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: episodes requiring active assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: episodes where the subject was able to treat her/himself and plasma glucose below 3.1 mmol/L, with or without symptoms. |
| Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26 | Week 26 | Mean of 9-point self-measured plasma glucose profile (SMPG) after week 26. Plasma glucose was measured before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before main evening meal, 90 minutes after the start of main evening meal, before bedtime, at 04:00 AM and before breakfast on the following day. |
Countries
Argentina, Brazil, Finland, India, Italy, Japan, North Macedonia, United Kingdom
Participant flow
Recruitment details
The trial was conducted at 55 sites in 7 countries: Brazil (2), Finland (8), India (10), Italy (6), Japan (15), Macedonia (1) and United Kingdom (13). For the extension trial, one trial site in Italy did not enroll any subject since approval was not obtained before the start of the trial from the IEC.
Pre-assignment details
All subjects who completed the 26-week main trial (NN1250-3585, NCT01074268) and were found to be eligible for the extension trial were offered to participate in the 26-week extension trial (NN1250-3725). The total duration of treatment was 52 weeks (26 weeks + 26 weeks), separated by 1 week of follow-up from the main trial.
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 OD was given for 26 weeks in the main period and for another 26 weeks in the extension period. | 302 |
| IDet OD Insulin detemir (IDet) was given subcutaneously (s.c.) once daily (OD) in the evening or twice daily (BID) morning and evening in combination with insulin aspart (IAsp) as meal-time insulin. IDet was given for 26 weeks in the main period and for another 26 weeks in the extension period. | 153 |
| Total | 455 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension: Week 27 to 52 (NN1250-3725) | Adverse Event | 1 | 1 |
| Extension: Week 27 to 52 (NN1250-3725) | Protocol Violation | 0 | 2 |
| Extension: Week 27 to 52 (NN1250-3725) | Unclassified | 3 | 2 |
| Extension: Week 27 to 52 (NN1250-3725) | Withdrawal criteria | 2 | 2 |
| Main: Week 0 to 26 (NN1250-3585) | Adverse Event | 3 | 1 |
| Main: Week 0 to 26 (NN1250-3585) | Lack of Efficacy | 0 | 2 |
| Main: Week 0 to 26 (NN1250-3585) | Protocol Violation | 3 | 4 |
| Main: Week 0 to 26 (NN1250-3585) | Unclassified | 8 | 5 |
| Main: Week 0 to 26 (NN1250-3585) | Withdrawal criteria | 6 | 3 |
Baseline characteristics
| Characteristic | IDet OD | Total | IDeg OD |
|---|---|---|---|
| Age, Continuous | 41.7 years STANDARD_DEVIATION 14.4 | 41.3 years STANDARD_DEVIATION 14.7 | 41.1 years STANDARD_DEVIATION 14.9 |
| Fasting plasma glucose (FPG) | 9.5 mmol/L STANDARD_DEVIATION 4 | 9.8 mmol/L STANDARD_DEVIATION 4 | 9.9 mmol/L STANDARD_DEVIATION 4 |
| Glycosylated haemoglobin (HbA1c) | 8.0 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.0 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.0 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 67 Participants | 219 Participants | 152 Participants |
| Sex: Female, Male Male | 86 Participants | 236 Participants | 150 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 185 / 301 | 89 / 152 |
| serious Total, serious adverse events | 36 / 301 | 11 / 152 |
Outcome results
Primary
Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs)
Rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no/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 or important medical issues
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 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 (AEs) | 459 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 20 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 23 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 48 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 388 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Fatal AE | 0 Events/100 years of patient exposure |
| IDet OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 341 Events/100 years of patient exposure |
| IDet OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AEs) | 420 Events/100 years of patient exposure |
| IDet OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 45 Events/100 years of patient exposure |
| IDet OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 17 Events/100 years of patient exposure |
| IDet OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Fatal AE | 0 Events/100 years of patient exposure |
| IDet OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 35 Events/100 years of patient exposure |
Primary
Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment
Change from baseline in HbA1c after 26 weeks of treatment
Time frame: Week 0, Week 26
Population: The full analysis set (FAS) included all randomised subjects and missing data was imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | -0.73 percentage of glycosylated haemoglobin | Standard Deviation 0.88 |
| IDet OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | -0.65 percentage of glycosylated haemoglobin | Standard Deviation 0.86 |
Secondary
Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment
Change from baseline in FPG after 52 weeks of treatment
Time frame: Week 0, Week 52
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 6 subjects change in FPG values were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | -2.19 mmol/L | Standard Deviation 4.99 |
| IDet OD | Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | -0.82 mmol/L | Standard Deviation 4.79 |
Secondary
Extension Trial (Secondary 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 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 52 Weeks of Treatment | -0.46 percentage of glycosylated haemoglobin | Standard Deviation 0.93 |
| IDet OD | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -0.47 percentage of glycosylated haemoglobin | Standard Deviation 0.88 |
Secondary
Extension 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) at week 52. Plasma glucose was measured before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before main evening meal, 90 minutes after the start of main evening meal, before bedtime, at 04:00 AM and before breakfast on the following day.
Time frame: Week 52
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 4 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 52 | 7.8 mmol/L | Standard Deviation 1.9 |
| IDet OD | Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 52 | 7.8 mmol/L | Standard Deviation 2 |
Secondary
Extension 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: episodes requiring active assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: episodes where the subject was able to treat her/himself and plasma glucose below 3.1 mmol/L with or without symptoms
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 in the main trial including subjects carried through to the extension trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD | Extension Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 3778 Episodes/100 years of patient exposure |
| IDet OD | Extension Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 3926 Episodes/100 years of patient exposure |
Secondary
Extension 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: episodes requiring active assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: episodes where subject was able to treat her/himself and plasma glucose below 3.1 mmol/L, with or without symptoms. 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 in the main trial including subjects carried through to the extension trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD | Extension Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 338 Episodes/100 years of patient exposure |
| IDet OD | Extension Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 481 Episodes/100 years of patient exposure |
Secondary
Main Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 26 Weeks of Treatment
Change from baseline in FPG after 26 weeks of treatment
Time frame: Week 0, Week 26
Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 6 subjects change in FPG values were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Main Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 26 Weeks of Treatment | -2.60 mmol/L | Standard Deviation 4.87 |
| IDet OD | Main Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 26 Weeks of Treatment | -0.62 mmol/L | Standard Deviation 4.49 |
Secondary
Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26
Mean of 9-point self-measured plasma glucose profile (SMPG) after week 26. Plasma glucose was measured before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before main evening meal, 90 minutes after the start of main evening meal, before bedtime, at 04:00 AM and before breakfast on the following day.
Time frame: Week 26
Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 5 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 26 | 7.9 mmol/L | Standard Deviation 2.1 |
| IDet OD | Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26 | 7.8 mmol/L | Standard Deviation 1.9 |
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: episodes requiring active assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: episodes where the subject was able to treat her/himself and plasma glucose below 3.1 mmol/L, with or without symptoms.
Time frame: Week 0 to Week 26 + 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 | 4583 Episodes/100 years of patient exposure |
| IDet OD | Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 4569 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: episodes requiring active assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: episodes where subject was able to treat her/himself and plasma glucose below 3.1 mmol/L, with or without symptoms. Nocturnal hypoglycaemic episodes are defined as occuring between 00:01 and 05:59 a.m.
Time frame: Week 0 to Week 26 + 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 | 414 Episodes/100 years of patient exposure |
| IDet OD | Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 593 Episodes/100 years of patient exposure |