Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Africa, Asia, Europe, and the United States of America (USA). The aim of this clinical trial is to compare NN1250 (insulin degludec (IDeg)) with insulin glargine (IGlar) plus insulin aspart (IAsp) with/without metformin and with/without pioglitazone in subjects with type 2 diabetes (main period) followed by investigating the long-term safety in terms of comparing NN1250 with insulin glargine plus insulin aspart with or without metformin and with or without pioglitazone in subjects with type 2 diabetes. All oral anti-diabetic drug (OAD) treatment will be discontinued, if applicable, when trial participant enters the trial (NN1250-3582) with the exception of metformin and pioglitazone. Subjects who consent to participate in the extension trial (NN1250-3667) will continue to receive the treatment to which they were randomly allocated in the 52 week trial NN1250-3582. The main period is registered internally at Novo Nordisk as NN1250-3582 while the extension period is registered as NN1250-3667.
Interventions
DRUGinsulin degludec
Injected subcutaneously (under the skin) with main evening meal. Dose was individually adjusted.
DRUGinsulin glargine
Injected subcutanoeusly (under the skin) according to approved label. Dose was individually adjusted.
DRUGinsulin aspart
Injected subcutaneously (under the skin) at each main meal. 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 MAIN period (NN1250-3582): * Type 2 diabetes mellitus for at least 6 months * Ongoing daily treatment with insulin (premix, self-mix, basal only, basal bolus) for at least 3 months with/without oral anti-diabetics drug (OAD) prior to trial start * HbA1c 7.0-10.0 % (both inclusive) * Body Mass Index (BMI) below or equal to 40.0 kg/m\^2 * For EXTENSION period (NN1250-3667): * Completion of the 52 week treatment period in NN1250-3582
Exclusion criteria
* For MAIN period (NN1250-3582): * Treatment with other insulin regimens than premix, self-mix, basal only, basal bolus 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 * 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 78 + 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 78 + 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. |
| Rate of Treatment Emergent Adverse Events (AEs) | Week 0 to Week 78 + 7 days follow up | Corresponds to rate of AEs per 100 patient years of exposure. Mild AEs: no or transient symptoms, no interference with subject's daily activities. Moderate AEs: marked symptoms, moderate interference with subject's daily activities. Severe AEs: considerable interference with subject's daily activities, unacceptable. Serious adverse event (SAE): 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 |
|---|---|---|
| Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 78 Weeks of Treatment | Week 0, Week 78 | Change from baseline in HbA1c after 78 weeks of treatment |
| 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. |
| 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 78 | Week 78 | Mean of the SMPG at 78 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, 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
Bulgaria, Germany, Hong Kong, Ireland, Italy, Romania, Russia, Slovakia, South Africa, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
The trial was conducted at 123 sites in 12 countries: Bulgaria (8 sites), Germany (8), Hong Kong (1), Ireland (4), Italy (11), Romania (5), Russia (6), Slovakia (4), South Africa (5), Spain (9), Turkey (3) and the United States (U.S.) (59). Some sites did not enroll subjects in the extension period. One site from United States was closed.
Pre-assignment details
All subjects who completed the 52-week main trial (NN1250-3582, NCT00972283) and were found to be eligible for the extension trial were offered to participate in the 26-week extension trial (NN1250-3667). The total duration of treatment was up to 78 weeks (52 weeks + 26 weeks).
Participants by arm
| Arm | Count |
|---|---|
| IDeg OD Insulin degludec (IDeg) was given subcutaneously once daily (OD) with main evening meal with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. The regimen was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period. | 744 |
| IGlar OD Insulin glargine (IGlar) was given subcutaneously once daily (OD), according to labelling instructions with insulin aspart (IAsp) as mealtime insulin with or without subject's pre-trial metformin with or without pioglitazone. IGlar was given for a treatment duration of 52 weeks in the main period and for an additional 26 weeks in the extension period. | 248 |
| Total | 992 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension: Week 53 to 78 (NN1250-3667) | Adverse Event | 4 | 0 |
| Extension: Week 53 to 78 (NN1250-3667) | Lack of Efficacy | 1 | 1 |
| Extension: Week 53 to 78 (NN1250-3667) | Protocol Violation | 5 | 0 |
| Extension: Week 53 to 78 (NN1250-3667) | Unclassified | 11 | 5 |
| Extension: Week 53 to 78 (NN1250-3667) | Withdrawal criteria | 6 | 2 |
| Main: Week 0 to 52 (NN1250-3582) | Adverse Event | 31 | 9 |
| Main: Week 0 to 52 (NN1250-3582) | Lack of Efficacy | 3 | 0 |
| Main: Week 0 to 52 (NN1250-3582) | Protocol Violation | 23 | 12 |
| Main: Week 0 to 52 (NN1250-3582) | Unclassified | 72 | 17 |
| Main: Week 0 to 52 (NN1250-3582) | Withdrawal criteria | 8 | 2 |
Baseline characteristics
| Characteristic | IDeg OD | IGlar OD | Total |
|---|---|---|---|
| Age, Continuous | 59.2 years STANDARD_DEVIATION 9.1 | 58.1 years STANDARD_DEVIATION 10 | 58.9 years STANDARD_DEVIATION 9.3 |
| Glycosylated Haemoglobin (HbA1c) | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.4 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 |
| Sex: Female, Male Female | 339 Participants | 115 Participants | 454 Participants |
| Sex: Female, Male Male | 405 Participants | 133 Participants | 538 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 447 / 753 | 146 / 251 |
| serious Total, serious adverse events | 139 / 753 | 53 / 251 |
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 78 + 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 | Value (NUMBER) |
|---|---|---|
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 1039 Episodes/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 1271 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 78 + 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 | 134 Episodes/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 176 Episodes/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: 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 | -1.17 percentage of glycosylated haemoglobin | Standard Deviation 1.03 |
| IGlar OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -1.29 percentage of glycosylated haemoglobin | Standard Deviation 0.98 |
Primary
Rate of Treatment Emergent Adverse Events (AEs)
Corresponds to rate of AEs per 100 patient years of exposure. Mild AEs: no or transient symptoms, no interference with subject's daily activities. Moderate AEs: marked symptoms, moderate interference with subject's daily activities. Severe AEs: considerable interference with subject's daily activities, unacceptable. Serious adverse event (SAE): 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 78 + 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 | Group | Value (NUMBER) |
|---|---|---|---|
| IDeg OD | Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 24 Events/100 years of patient exposure |
| IDeg OD | Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AEs) | 411 Events/100 years of patient exposure |
| IDeg OD | Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 20 Events/100 years of patient exposure |
| IDeg OD | Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 113 Events/100 years of patient exposure |
| IDeg OD | Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 274 Events/100 years of patient exposure |
| IDeg OD | Rate of Treatment Emergent Adverse Events (AEs) | Fatal AE | 1 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 266 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 118 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AEs) | 403 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Fatal AE | 1 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 20 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 20 Events/100 years of patient exposure |
Secondary
Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 78 Weeks of Treatment
Change from baseline in HbA1c after 78 weeks of treatment
Time frame: Week 0, Week 78
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 78 Weeks of Treatment | -0.95 percentage of glycosylated haemoglobin | Standard Deviation 1.13 |
| IGlar OD | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 78 Weeks of Treatment | -1.15 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 78
Mean of the SMPG at 78 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, before breakfast.
Time frame: Week 78
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 36 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 78 | 7.2 mmol/L | Standard Deviation 1.9 |
| IGlar OD | Extension Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 78 | 6.8 mmol/L | Standard Deviation 1.4 |
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 36 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 | 7.3 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 | 6.9 mmol/L | Standard Deviation 1.5 |
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 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 | 1109 Episodes/100 years of patient exposure |
| IGlar OD | Main Trial (Secondary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 1363 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 | 139 Episodes/100 years of patient exposure |
| IGlar OD | Main Trial (Secondary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 184 Episodes/100 years of patient exposure |