Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Japan. The aim of this trial is to investigate the efficacy and safety of NN5401 (insulin degludec/insulin aspart) with insulin glargine in subjects with type 2 diabetes in Japan. Depending on pre-trial oral anti-diabetic drugs (OADs), subjects continued at the same dose and dosing frequency.
Interventions
DRUGinsulin degludec/insulin aspart
Injected subcutaneously (under the skin) once daily prior to the largest meal of the day as monotherapy or combined with no more than 2 oral anti-diabetic drugs (OADs).
DRUGinsulin glargine
Administered according to approved labelling either as monotherapy or combined with no more than 2 OADs.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus (diagnosed clinically) for at least 6 months * HbA1c 7.0-10.0% (both inclusive) by central laboratory analysis * Body Mass Index (BMI) below or equal to 35.0 kg/m\^2 * Insulin naive subject and ongoing treatment with 1 or more oral antidiabetic drugs (OADs) for at least 12 weeks prior to randomisation with at least recommended maintenance dose according to local, approved labelling Allowed are: a. Previous short term insulin treatment up to 14 days; b. Treatment during hospitalization or during gestational diabetes is allowed for periods longer than 14 days)
Exclusion criteria
* Anticipated change in concomitant medication known to interfere significantly with glucose metabolism, such as systemic corticosteroids, beta-blockers, mono amino oxidase (MAO) inhibitors * Use of glucagon-like peptide-1 (GLP-1) receptor agonists, buformine and/or rosiglitazone within the last 12 weeks prior to randomisation * Cardiovascular disease, within the last 6 months prior to Visit 1, defined as: stroke; decompensated heart failure New York Heart Association (NYHA) class III or IV; myocardial infarction; unstable angina pectoris; or coronary arterial bypass graft or angioplasty
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) | Week 0, Week 26 | Observed change from baseline in HbA1c after 26 weeks of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Increment of 9-point Self Measured Plasma Glucose Profile (SMPG) at the Main Evening Meal | Week 26 | Observed mean increment of the 9-point self-measured plasma glucose profile (SMPG) at the main evening meal |
| Rate of Treatment Emergent Adverse Events (AEs) | Week 0 to Week 26 + 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 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. |
| Rate of Confirmed Hypoglycaemic Episodes | Week 0 to Week 26 + 7 days follow up | Observed 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. |
| Rate of Nocturnal Confirmed Hypoglycaemic Episodes | Week 0 to Week 26 + 7 days follow up | Observed 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. |
| Change in Body Weight | Week 0, Week 26 | Observed change from baseline in body weight after 26 weeks of treatment |
Countries
Japan
Participant flow
Recruitment details
The trial was conducted at 48 sites in Japan.
Pre-assignment details
Subjects continued on not more than 2 oral antidiabetic drugs (excluding sulphonylureas/dipeptyl peptidase-4 \[DPP-4\] inhibitors/glinides) at the pre-randomisation dose level and dosing frequency.
Participants by arm
| Arm | Count |
|---|---|
| IDegAsp OD Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously once daily (OD) either as monotherapy or in combination with no more than 2 oral antidiabetic drugs (excluding sulphonylureas/DPP-4 inhibitors/glinides). IDegAsp was given just prior to the largest meal of the day. Insulin doses were individually adjusted. | 147 |
| IGlar OD Insulin glargine (IGlar) was given once daily (OD) according to approved labelling either as monotherapy or in combination with no more than 2 oral antidiabetic drugs (excluding sulphonylureas/DPP-4 inhibitors/glinides). IGlar was given before breakfast or at bedtime but at the same time each day. Insulin doses were individually adjusted. | 149 |
| Total | 296 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 3 |
| Overall Study | Unclassified | 8 | 7 |
| Overall Study | Withdrawal Criteria | 1 | 1 |
Baseline characteristics
| Characteristic | IDegAsp OD | IGlar OD | Total |
|---|---|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 10 | 61.0 years STANDARD_DEVIATION 9.6 | 60.5 years STANDARD_DEVIATION 9.8 |
| Body weight | 66.2 kg STANDARD_DEVIATION 13.4 | 66.4 kg STANDARD_DEVIATION 13.3 | 66.3 kg STANDARD_DEVIATION 13.4 |
| Fasting plasma glucose (FPG) | 9.0 mmol/L STANDARD_DEVIATION 1.6 | 9.1 mmol/L STANDARD_DEVIATION 1.9 | 9.0 mmol/L STANDARD_DEVIATION 1.7 |
| Glycosylated haemoglobin (HbA1c) | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.5 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.4 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 |
| Sex: Female, Male Female | 57 Participants | 50 Participants | 107 Participants |
| Sex: Female, Male Male | 90 Participants | 99 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 147 | 47 / 149 |
| serious Total, serious adverse events | 5 / 147 | 3 / 149 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c)
Observed change from baseline in HbA1c after 26 weeks of treatment
Time frame: Week 0, Week 26
Population: 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 | Change in Glycosylated Haemoglobin (HbA1c) | -1.35 percentage of glycosylated haemoglobin | Standard Deviation 0.86 |
| IGlar OD | Change in Glycosylated Haemoglobin (HbA1c) | -1.22 percentage of glycosylated haemoglobin | Standard Deviation 0.98 |
Secondary
Change in Body Weight
Observed change from baseline in body weight after 26 weeks of treatment
Time frame: Week 0, Week 26
Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator. Missing data is imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp OD | Change in Body Weight | 0.7 kg | Standard Deviation 2.8 |
| IGlar OD | Change in Body Weight | 0.7 kg | Standard Deviation 2.2 |
Secondary
Mean Increment of 9-point Self Measured Plasma Glucose Profile (SMPG) at the Main Evening Meal
Observed mean increment of the 9-point self-measured plasma glucose profile (SMPG) at the main evening meal
Time frame: Week 26
Population: 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 | Mean Increment of 9-point Self Measured Plasma Glucose Profile (SMPG) at the Main Evening Meal | 1.4 mmol/L | Standard Deviation 4.2 |
| IGlar OD | Mean Increment of 9-point Self Measured Plasma Glucose Profile (SMPG) at the Main Evening Meal | 4.7 mmol/L | Standard Deviation 3.6 |
Secondary
Rate of Confirmed Hypoglycaemic Episodes
Observed 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: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp OD | Rate of Confirmed Hypoglycaemic Episodes | 191 Episodes/100 years of patient exposure |
| IGlar OD | Rate of Confirmed Hypoglycaemic Episodes | 271 Episodes/100 years of patient exposure |
Secondary
Rate of Nocturnal Confirmed Hypoglycaemic Episodes
Observed 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: 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 | Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 39 Episodes/100 years of patient exposure |
| IGlar OD | Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 53 Episodes/100 years of patient exposure |
Secondary
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 26 + 7 days follow up
Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDegAsp OD | Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AEs) | 334 Events/100 years of patient exposure |
| IDegAsp OD | Rate of Treatment Emergent Adverse Events (AEs) | Serious AEs | 7 Events/100 years of patient exposure |
| IDegAsp OD | Rate of Treatment Emergent Adverse Events (AEs) | Severe AEs | 1 Events/100 years of patient exposure |
| IDegAsp OD | Rate of Treatment Emergent Adverse Events (AEs) | Moderate AEs | 17 Events/100 years of patient exposure |
| IDegAsp OD | Rate of Treatment Emergent Adverse Events (AEs) | Mild AEs | 316 Events/100 years of patient exposure |
| IDegAsp OD | Rate of Treatment Emergent Adverse Events (AEs) | Fatal AEs | 0 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Mild AEs | 353 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AEs) | 368 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Moderate AEs | 14 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Serious AEs | 4 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Fatal AEs | 0 Events/100 years of patient exposure |
| IGlar OD | Rate of Treatment Emergent Adverse Events (AEs) | Severe AEs | 0 Events/100 years of patient exposure |