Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted in Europe, Oceania, and the United States of America (USA). The aim of this clinical trial is to compare NN5401 (insulin degludec/insulin aspart (IDegAsp)) with insulin detemir (IDet) plus insulin aspart in patients with type 1 diabetes (main period) followed by the extension period comparing the long-term safety of NN5401 plus insulin aspart with insulin detemir plus insulin aspart. The main period is registered internally at Novo Nordisk as NN5401-3594 while the extension period is registered as NN5401-3645.
Interventions
DRUGinsulin degludec/insulin aspart
Injected subcutaneously (under the skin) once daily with a meal. Dose was individually adjusted.
DRUGinsulin detemir
Injected subcutaneously (under the skin) once daily or twice daily. Dose was individually adjusted.
DRUGinsulin aspart
Injected subcutaneously (under the skin) at the remaining meals. 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
* FOR THE MAIN TRIAL, NN5401-3594: * Type 1 diabetes mellitus for at least 12 months * Ongoing daily treatment with insulin (in a basal bolus regimen, premix insulin regimen, self mix regimen) for at least 12 months * HbA1c 7.0-10.0% (both inclusive) * BMI (Body Mass Index) below or equal to 35.0 kg/m\^2 * FOR THE EXTENSION TRIAL, NN5401-3645: * The subject must have completed the six-month treatment period in trial NN5401-3594
Exclusion criteria
* FOR THE MAIN TRIAL, NN5401-3594: * Treatment with other insulin regimens than insulin in a basal bolus regimen/premix insulin regimen/self mix regimen within 3 months * Cardiovascular disease within the last 6 months * Uncontrolled treated/untreated severe hypertension * Pregnancy, breast-feeding, the intention of becoming pregnant or not using adequate contraceptive measures according to local requirements * Cancer and medical history of cancer * FOR THE EXTENSION TRIAL, NN5401-3645: * Anticipated significant lifestyle changes during the trial * Pregnancy, breast-feeding, the intention of becoming pregnant or not using adequate contraceptive measures
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 Confirmed Hypoglycaemic Episodes | Week 0 to Week 53 + 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 were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol /L. |
| Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | Week 0 to Week 53 + 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 were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes were defined as occurring between 00:01 and 05:59 a.m. |
| Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Week 0 to Week 53 + 7 days of 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. |
| Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | Week 0, Week 53 | Change from baseline in FPG after 52 weeks of treatment. |
| Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26 | Week 26 | Overall mean of 9-point SMPG at 26 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 52 Weeks of Treatment | Week 0, Week 53 | 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 were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes were defined as occurring between 00:01 and 05:59 a.m. |
Countries
Australia, Denmark, France, Israel, Poland, Puerto Rico, Romania, Russia, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 79 sites in 9 countries: Denmark (3 sites), Poland (6 sites), Romania (8 sites), France (3 sites), United Kingdom (8 sites), Russian Federation (11 sites), Israel (4 sites), Australia (7 sites), and United States (29 sites). Some sites did not enrol subjects in the extension period.
Pre-assignment details
The total duration of treatment was up to 52 weeks (26 weeks \[main trial: NN5401-3594, NCT00978627\] + 26 weeks \[extension trial: NN5401-3645\]), separated by 1 week of wash-out period; during which subjects were treated with Neutral Protamine Hagedorn (NPH) insulin twice daily (BID) in combination with insulin aspart.
Participants by arm
| Arm | Count |
|---|---|
| IDegAsp OD Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) with a main meal in combination with mealtime insulin aspart (IAsp) for the remaining meals. The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period. | 366 |
| IDet Insulin detemir (Idet) was given subcutaneously (s.c) once daily (OD) in the evening or twice daily (BID) in combination with mealtime insulin aspart (Iasp). The regimen was given for 26 weeks in the main period and for an additional 26 weeks in the extension period. | 182 |
| Total | 548 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension: Week 27 to 52 (NN5401-3645) | Adverse Event | 3 | 0 |
| Extension: Week 27 to 52 (NN5401-3645) | Protocol Violation | 4 | 1 |
| Extension: Week 27 to 52 (NN5401-3645) | Unclassified | 12 | 7 |
| Extension: Week 27 to 52 (NN5401-3645) | Withdrawal criteria | 2 | 1 |
| Main: Week 0 to 26 (NN5401-3594) | Adverse Event | 4 | 3 |
| Main: Week 0 to 26 (NN5401-3594) | Lack of Efficacy | 2 | 0 |
| Main: Week 0 to 26 (NN5401-3594) | Protocol Violation | 8 | 6 |
| Main: Week 0 to 26 (NN5401-3594) | Unclassified | 25 | 12 |
| Main: Week 0 to 26 (NN5401-3594) | Withdrawal criteria | 7 | 5 |
Baseline characteristics
| Characteristic | IDegAsp OD | IDet | Total |
|---|---|---|---|
| Age, Continuous | 40.7 years STANDARD_DEVIATION 12.8 | 42.6 years STANDARD_DEVIATION 13.8 | 41.3 years STANDARD_DEVIATION 13.2 |
| Fasting plasma glucose (FPG) | 10.3 mmol/L STANDARD_DEVIATION 4.7 | 11.0 mmol/L STANDARD_DEVIATION 4.8 | 10.5 mmol/L STANDARD_DEVIATION 4.8 |
| Glycosylated haemoglobin (HbA1c) | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.7 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 |
| Sex: Female, Male Female | 176 Participants | 100 Participants | 276 Participants |
| Sex: Female, Male Male | 190 Participants | 82 Participants | 272 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 166 / 362 | 90 / 180 |
| serious Total, serious adverse events | 46 / 362 | 20 / 180 |
Outcome results
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 were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol /L.
Time frame: Week 0 to Week 53 + 7 days follow up
Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 3183 Episodes/100 years of patient exposure |
| IDet | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 3673 Episodes/100 years of patient exposure |
Primary
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 were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes were defined as occurring between 00:01 and 05:59 a.m.
Time frame: Week 0 to Week 53 + 7 days follow up
Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 309 Episodes/100 years of patient exposure |
| IDet | Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 541 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 53 + 7 days of follow up
Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 93 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 33 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 282 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 24 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Fatal AE | 0 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Adverse event (AE) | 408 Events/100 years of patient exposure |
| IDet | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Fatal AE | 0 Events/100 years of patient exposure |
| IDet | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Adverse event (AE) | 442 Events/100 years of patient exposure |
| IDet | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 48 Events/100 years of patient exposure |
| IDet | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 83 Events/100 years of patient exposure |
| IDet | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 311 Events/100 years of patient exposure |
| IDet | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 19 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 were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | -0.73 percentage of glycosylated haemoglobin | Standard Deviation 0.83 |
| IDet | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | -0.68 percentage of glycosylated haemoglobin | Standard Deviation 0.77 |
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 53
Population: The full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). For 2 subjects, FPG values were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp OD | Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | -1.83 mmol/L | Standard Deviation 5.69 |
| IDet | Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | -2.40 mmol/L | Standard Deviation 5.86 |
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 53
Population: The full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp OD | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -0.65 percentage of glycosylated haemoglobin | Standard Deviation 0.81 |
| IDet | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -0.56 percentage of glycosylated haemoglobin | Standard Deviation 0.8 |
Secondary
Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26
Overall mean of 9-point SMPG at 26 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 26
Population: The full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). For 22 subjects all 9-point SMPG values were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp OD | Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26 | 8.0 mmol/L | Standard Deviation 2.2 |
| IDet | Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26 | 8.4 mmol/L | Standard Deviation 2.5 |
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 were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L.
Time frame: Week 0 to Week 26 + 7 days follow up
Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp OD | Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 3917 Episodes/100 years of patient exposure |
| IDet | Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 4434 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 were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes were defined as occurring between 00:01 and 05:59 a.m.
Time frame: Week 0 to Week 26 + 7 days follow up
Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp OD | Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 371 Episodes/100 years of patient exposure |
| IDet | Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 572 Episodes/100 years of patient exposure |