Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe and the United States of America (USA). The aim of this trial is to compare NN1250 (insulin degludec (IDeg)) with insulin glargine (IGlar) in subjects with type 2 diabetes never treated with insulin followed by the extension trial investigating the long-term safety and tolerability in terms of comparing NN1250 with insulin glargine in subjects with type 2 diabetes. All oral anti-diabetic drug (OAD) treatment will be discontinued when trial participant enters the main trial (NN1250-3579) with the exception of metformin and dipeptidyl peptidase-IV (DPP-IV) inhibitor treatment (only in countries where DPP-IV inhibitor treatment is approved for combination treatment together with insulin, otherwise DPP-IV inhibitor treatment is also discontinued). Subjects who consent to participate in the extension trial will continue the treatment (NN1250 or insulin glargine + oral antidiabetic drugs (OADs)) to which they were randomly allocated in the 52 week main trial. The main period is registered internally at Novo Nordisk as NN1250-3579 while the extension period is registered as NN1250-3643.
Interventions
DRUGinsulin degludec
Injected subcutaneously (under the skin) once daily. Dose was individually adjusted.
DRUGinsulin glargine
Injected subcutaneously (under the skin) once daily. 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 2 diabetes mellitus * Treatment with oral antidiabetic drugs (OADs) for at least three months before trial start at an unchanged dose * HbA1c: 7.0-10.0% * Body Mass Index (BMI) no higher than 40.0 kg/m\^2 * For the extension trial only: Completion of the 52 week treatment period in trial NN1250-3579 (NCT00982644)
Exclusion criteria
* Treatment with exenatide or liraglutide within the last 3 months before trial start * 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 * 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 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): 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 occurring between 00:01 and 05:59 a.m. |
| Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Week 0 to Week 104 + 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 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. |
| 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 occurring between 00:01 and 05:59 a.m. |
| 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 |
| Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 52 | Week 52 | Mean of 9-point SMPG at 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): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 104 | Week 104 | Mean of 9-point SMPG at 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. |
Countries
Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Norway, Puerto Rico, Serbia, Serbia and Montenegro, Slovenia, Spain, United States
Participant flow
Recruitment details
The trial was conducted at 166 sites in 12 countries: Austria (6 sites), Belgium (5 sites), Canada (17 sites), Czech Republic (5 sites), Denmark (6 sites), Finland (6 sites), France (7 sites), Germany (16 sites), Norway (8 sites), Serbia (5 sites), Spain (9 sites) and United States (76 sites). Some subjects did not enrol in the extension period.
Pre-assignment details
All subjects who completed the 52-week main trial (NN51250-3579, NCT00982644) and when found to be eligible for the extension trial, were offered to participate in the 52-week extension trial (NN1250-3643). The total duration of treatment was up to 104 weeks (52 weeks + 52 weeks).
Participants by arm
| Arm | Count |
|---|---|
| IDeg OD Insulin degludec (IDeg) was given subcutaneously (s.c) once daily (OD) with the main evening meal in combination with metformin with or without DPP-IV inhibitors. IDeg was given for 52 weeks in the main period and for another 52 weeks in the extension period. | 773 |
| IGlar OD Insulin glargine (IGlar) was given subcutaneously (s.c) once daily (OD), according to the local labelling in combination with metformin with or without DPP-IV inhibitors. IGlar was given for 52 weeks in the main period and for another 52 weeks in the extension period. | 257 |
| Total | 1,030 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension: Week 53 to 104 (NN1250-3643) | Adverse Event | 12 | 5 |
| Extension: Week 53 to 104 (NN1250-3643) | Lack of Efficacy | 3 | 1 |
| Extension: Week 53 to 104 (NN1250-3643) | Protocol Violation | 2 | 4 |
| Extension: Week 53 to 104 (NN1250-3643) | Unclassified | 23 | 7 |
| Extension: Week 53 to 104 (NN1250-3643) | Withdrawal criteria | 6 | 3 |
| Main: Week 0 to 52 (NN1250-3579) | Adverse Event | 20 | 5 |
| Main: Week 0 to 52 (NN1250-3579) | Lack of Efficacy | 7 | 2 |
| Main: Week 0 to 52 (NN1250-3579) | Protocol Violation | 46 | 18 |
| Main: Week 0 to 52 (NN1250-3579) | Unclassified | 84 | 30 |
| Main: Week 0 to 52 (NN1250-3579) | Withdrawal criteria | 9 | 5 |
Baseline characteristics
| Characteristic | IDeg OD | IGlar OD | Total |
|---|---|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 9.7 | 58.7 years STANDARD_DEVIATION 9.9 | 59.1 years STANDARD_DEVIATION 9.8 |
| Fasting plasma glucose (FPG) | 9.6 mmol/L STANDARD_DEVIATION 2.6 | 9.7 mmol/L STANDARD_DEVIATION 2.6 | 9.7 mmol/L STANDARD_DEVIATION 2.6 |
| Gender Female | 302 Participants | 90 Participants | 392 Participants |
| Gender Male | 471 Participants | 167 Participants | 638 Participants |
| Glycosylated haemoglobin (HbA1c) | 8.2 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.2 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.2 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 463 / 766 | 153 / 257 |
| serious Total, serious adverse events | 116 / 766 | 41 / 257 |
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 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 | 172 Episodes/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 205 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 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 occurring 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 | 27 Episodes/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 46 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 of 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 event (AE) | 362 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 15 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 14 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 93 Events/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 254 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 |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 234 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Adverse event (AE) | 339 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 87 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 | 17 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 last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -1.06 percentage of glycosylated haemoglobin | Standard Deviation 1.01 |
| IGlar OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -1.19 percentage of glycosylated haemoglobin | Standard Deviation 0.97 |
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 | -0.95 percentage of glycosylated haemoglobin | Standard Deviation 1.04 |
| IGlar OD | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment | -1.11 percentage of glycosylated haemoglobin | Standard Deviation 0.99 |
Secondary
Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 104
Mean of 9-point SMPG at 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: 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 140 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 | 7.6 mmol/L | Standard Deviation 1.9 |
| IGlar OD | Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 104 | 7.6 mmol/L | Standard Deviation 1.9 |
Secondary
Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 52
Mean of 9-point SMPG at 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 126 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 | 7.7 mmol/L | Standard Deviation 1.8 |
| IGlar OD | Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 52 | 7.7 mmol/L | Standard Deviation 2 |
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 safety analysis set (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 | 152 Episodes/100 years of patient exposure |
| IGlar OD | Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 185 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 occurring 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 | 25 Episodes/100 years of patient exposure |
| IGlar OD | Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 39 Episodes/100 years of patient exposure |