Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia, Europe and the United States of America (USA). The aim of this trial is to compare the efficacy and safety of NN5401 (insulin degludec/insulin aspart (IDegAsp)) with insulin glargine (IGlar), both as add-on to subject's ongoing treatment with metformin + at least one OAD (oral anti-diabetic drug). The main period is registered internally at Novo Nordisk as NN5401-3590 while the extension period is registered as NN5401-3726.
Interventions
DRUGinsulin degludec/insulin aspart
Injected s.c. (under the skin) once daily with the breakfast meal. Dose was individually adjusted.
DRUGinsulin glargine
Injected s.c. (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
* For MAIN period (NN5401-3590): * Diagnosis of type 2 diabetes mellitus for at least 6 months * Insulin naïve subjects * Treatment with metformin and at least one other oral antidiabetic drug for at least 3 months before trial start * Glycosylated haemoglobin (HbA1c) between 7.5 - 11.0% (both inclusive) * Body Mass Index (BMI) no higher than 40.0 kg/m\^2 * For EXTENSION period (NN5401-3726): * Informed consent obtained before any trial-related activities * Must have completed the 26-week treatment period (visit 28) in trial NN5401-3590
Exclusion criteria
* For MAIN period (NN5401-3590): * Treatment with glucagon like peptide-1 (GLP-1) receptor agonists and/or thiazolidinedione(s) within the last 3 months prior to trial start * Cardiovascular disease diagnosed within 6 months before trial start * For EXTENSION period (NN5401-3726): * Anticipated change in concomitant medication known to interfere significantly with glucose metabolism, such as systemic corticosteroids, beta-blockers, Monoamine oxidase (MAO) inhibitors * Anticipated significant lifestyle changes during the trial, e.g. shift work (including permanent night/evening shift workers), as well as highly variable eating habits as judged by the physician) * Pregnancy, breast-feeding, the intention of becoming pregnant or not using adequate contraceptive measures according to local requirements
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 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 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 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 53 + 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 the subject's daily activities. Moderate: marked symptoms, moderate interference with the subject's daily activities. Severe: considerable interference with the 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 hospitalisation/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 52 Weeks of Treatment | Week 0, Week 53 | Change from baseline in HbA1c after 52 weeks of treatment. |
| Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26 | Week 26 | Mean of 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. |
Countries
Austria, India, Poland, Puerto Rico, Russia, South Korea, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
The trial was conducted at 88 sites in 8 countries: Austria (4), India (7), South Korea (5), Poland (6), Russia (10), Spain (11), Turkey (5), and United States of America (40). Some sites did not enroll subjects in the extension period.
Pre-assignment details
The total duration of treatment was up to 52 weeks (26 weeks \[main trial: NN5401-3590, NCT01045707\] + 26 weeks \[extension trial: NN5401-3726\]), 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 subject's pre-trial treatment of metformin.
Participants by arm
| Arm | Count |
|---|---|
| IDegAsp OD Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously (s.c.) once daily (OD) in combination with subject's pre-trial treatment of metformin. IDegAsp was given with breakfast for 26 weeks in the main period and with either breakfast or with the largest meal for another 26 weeks in the extension period. | 266 |
| IGlar OD Insulin glargine (IGlar) was given subcutaneously (s.c.) once daily (OD) according to approved labelling in combination with subject's pre-trial treatment of metformin. IGlar was given for 52 weeks (26 weeks in main period and 26 weeks in extension period). | 263 |
| Total | 529 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension: Week 27 to 52 (NN5401-3726) | Adverse Event | 3 | 3 |
| Extension: Week 27 to 52 (NN5401-3726) | Protocol Violation | 2 | 3 |
| Extension: Week 27 to 52 (NN5401-3726) | Unclassified | 6 | 5 |
| Extension: Week 27 to 52 (NN5401-3726) | Withdrawal criteria | 2 | 1 |
| Main: Week 0 to 26 (NN5401-3590) | Adverse Event | 5 | 3 |
| Main: Week 0 to 26 (NN5401-3590) | Lack of Efficacy | 4 | 2 |
| Main: Week 0 to 26 (NN5401-3590) | Protocol Violation | 6 | 5 |
| Main: Week 0 to 26 (NN5401-3590) | Unclassified | 10 | 11 |
| Main: Week 0 to 26 (NN5401-3590) | Withdrawal Criteria | 22 | 11 |
Baseline characteristics
| Characteristic | IDegAsp OD | IGlar OD | Total |
|---|---|---|---|
| Age, Continuous | 57.4 years STANDARD_DEVIATION 9 | 56.4 years STANDARD_DEVIATION 9.2 | 56.9 years STANDARD_DEVIATION 9.1 |
| Fasting plasma glucose (FPG) | 10.1 mmol/L STANDARD_DEVIATION 2.9 | 10.4 mmol/L STANDARD_DEVIATION 2.8 | 10.2 mmol/L STANDARD_DEVIATION 2.9 |
| Gender Female | 141 Participants | 127 Participants | 268 Participants |
| Gender Male | 125 Participants | 136 Participants | 261 Participants |
| Glycosylated haemoglobin (HbA1c) | 8.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1 | 8.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 88 / 265 | 79 / 261 |
| serious Total, serious adverse events | 30 / 265 | 15 / 261 |
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 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 | 419 Episodes/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 211 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 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 | 19 Episodes/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 53 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 the subject's daily activities. Moderate: marked symptoms, moderate interference with the subject's daily activities. Severe: considerable interference with the 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 hospitalisation/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect
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 | Group | Value (NUMBER) |
|---|---|---|---|
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AE) | 313 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 17 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Severe AE | 9 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 77 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 227 Events/100 years of patient exposure |
| IDegAsp OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Fatal AE | 2 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Mild AE | 162 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AE) | 238 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Moderate AE | 66 Events/100 years of patient exposure |
| IGlar OD | Extension Trial (Primary Endpoint): Rate of Treatment Emergent Adverse Events (AEs) | Serious AE | 9 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 | 10 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). One subject was excluded from FAS because the subject was randomised in error and was not dosed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | -1.65 percentage of glycosylated haemoglobin | Standard Deviation 1.28 |
| IGlar OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | -1.72 percentage of glycosylated haemoglobin | Standard Deviation 1.17 |
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). One subject was excluded from FAS because the subject was randomised in error and was not dosed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp OD | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -1.39 percentage of glycosylated haemoglobin | Standard Deviation 1.23 |
| IGlar OD | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -1.34 percentage of glycosylated haemoglobin | Standard Deviation 1.16 |
Secondary
Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26
Mean of 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). One subject was excluded from FAS because the subject was randomised in error and was not dosed. For 24 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 | 7.9 mmol/L | Standard Deviation 2.1 |
| IGlar OD | Main Trial (Secondary Endpoint): Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) at Week 26 | 7.9 mmol/L | Standard Deviation 1.7 |