Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Africa, Asia and Europe. The aim of the trial is to compare the efficacy and safety of insulin degludec/insulin aspart and BIAsp 30 (biphasic insulin aspart 30) in insulin naïve subjects with type 2 diabetes.
Interventions
DRUGinsulin degludec/insulin aspart
Administered s.c. (under the skin) twice daily. Dose individually adjusted. Pre-trial metformin treatment to be continued.
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
* Informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject) * Type 2 diabetes mellitus (diagnosed clinically) for at least 24 weeks prior to screening * Current treatment: metformin monotherapy or metformin in any combination with one of the following oral anti-diabetic drugs (OADs): insulin secretagogue (sulfonylurea or glinide), dipeptidyl peptidase IV (DPP-IV) inhibitor, alpha-glucosidase inhibitors for at least 12 weeks prior to randomisation (Visit 2) with the minimum doses stated: - Metformin: alone or in combination (including fixed combination) 1500 mg daily, or maximum tolerated dose (at least 1000 mg daily), - Insulin secretagogue (sulphonylurea or glinide): minimum half of the daily maximum dose according to local labelling, - DPP-IV inhibitor: minimum 100 mg daily or according to local labelling, - Alpha-glucosidase-inhibitors: minimum half of the daily maximum dose or maximum tolerated dose * Insulin naïve subject; allowed is: Previous short term insulin treatment up to 14 days * Insulin naïve subject; allowed is: Treatment during hospitalization or during gestational diabetes is allowed for periods longer than 14 days) * HbA1c (glycosylated haemoglobin) between 7.0-10.0 % (both inclusive) by central laboratory analysis * Body mass index (BMI) below or equal to 40.0 kg/m\^2
Exclusion criteria
* Treatment with thiazolidinediones (TZDs) or glucagon like peptide 1 (GLP-1) receptor agonists within 12 weeks prior to visit 1 (screening) * Anticipated change in concomitant medication known to interfere significantly with glucose metabolism, such as systemic corticosteroids, beta-blockers and MAO inhibitors * Anticipated significant lifestyle changes during the trial according to the discretion of the trial physician, e.g. shift work (including permanent night/evening shift workers), as well as highly variable eating habits * Cardiovascular disease, within the last 24 weeks prior to trial start, defined as: stroke; decompensated heart failure NYHA (New York Heart Association) class III or IV; myocardial infarction; unstable angina pectoris; or coronary arterial bypass graft or angioplasty * Any clinically significant disease or disorder, except for conditions associated with type 2 diabetes, which in the trial physician's opinion could interfere with the results of the trial * Previous participation in this trial. Participation is defined as randomised. Re-screening of screening failures is allowed only once within the limits of the recruitment period * Known or suspected hypersensitivity to trial products or related products
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0, week 26 | Change from baseline in HbA1c after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Nocturnal (00:01-05:59 am) Severe or Minor Hypoglycaemic Episodes | Onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product | The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes, which is presented here. 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 am. |
| Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | Onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product | The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes, which is presented here. 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. |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Week 0, week 26 | Change from baseline in fasting plasma glucose (FPG) after 26 weeks of treatment. |
| Responder for HbA1c (Below 7.0%) Without Severe and Minor Treatment Emergent Hypoglycaemic Episodes During the Last 12 Weeks of Treatment Including Only Subjects Exposed for at Least 12 Weeks | Week 26 | Responder for HbA1c (\<7.0%) without severe and minor treatment emergent hypoglycaemic episodes during the last 12 weeks of treatment. Severe + minor hypoglycaemic episodes = confirmed hypoglycaemic episodes. Severe hypoglycaemic episodes: requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: able to treat her/himself and plasma glucose below 3.1 mmol/L. |
| Number of Treatment Emergent AEs (Adverse Events) | Onset on or after the first day of exposure to investigational product and no later than 7 days after exposure to investigational product | A Treatment Emergent Adverse Event (TEAE) was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. Severity was assessed by investigator. |
| Change From Baseline in Body Weight | Week 0, week 26 | Change from baseline in body weight after 26 weeks of treatment. |
Countries
Algeria, Bulgaria, Croatia, Czechia, Germany, Poland, Romania, Slovakia, Turkey (Türkiye), Ukraine
Participant flow
Recruitment details
The trial was conducted at 47 sites in 10 countries: Algeria (4), Bulgaria (7), Croatia (5), Czech Republic (4), Germany (5), Poland (5), Romania (5), Slovakia (3), Turkey (2), and Ukraine (7).
Pre-assignment details
Subjects continued their metformin monotherapy or metformin in any combination with one of the following OADs: insulin secretagogue (sulphonylurea or glinide), dipeptidyl peptidase IV (DPP-IV) inhibitor, α-glucosidase inhibitors for at least 12 weeks prior to randomisation.
Participants by arm
| Arm | Count |
|---|---|
| IDegAsp BID Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with metformin. IDegAsp was given with the breakfast meal and main evening meal. | 197 |
| BIAsp 30 BID Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with metformin. BIAsp 30 was given with the breakfast meal and main evening meal. | 197 |
| Total | 394 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Unclassified | 5 | 10 |
| Overall Study | Withdrawal Criteria | 3 | 0 |
Baseline characteristics
| Characteristic | IDegAsp BID | BIAsp 30 BID | Total |
|---|---|---|---|
| Age, Continuous | 59.0 years STANDARD_DEVIATION 9.5 | 58.8 years STANDARD_DEVIATION 8.4 | 58.9 years STANDARD_DEVIATION 8.9 |
| Body Weight | 88.0 kg STANDARD_DEVIATION 15 | 88.5 kg STANDARD_DEVIATION 14.9 | 88.2 kg STANDARD_DEVIATION 14.9 |
| Fasting plasma glucose (FPG) | 10.5 mmol/L STANDARD_DEVIATION 2.4 | 10.0 mmol/L STANDARD_DEVIATION 2.3 | 10.2 mmol/L STANDARD_DEVIATION 2.3 |
| Glycosylated Haemoglobin (HbA1c) | 8.5 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.3 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.7 | 8.4 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.8 |
| Sex: Female, Male Female | 95 Participants | 96 Participants | 191 Participants |
| Sex: Female, Male Male | 102 Participants | 101 Participants | 203 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 196 | 7 / 195 |
| serious Total, serious adverse events | 13 / 196 | 10 / 195 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin)
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. Missing data were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp BID | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -1.85 Percent (%) glycosylated haemoglobin | Standard Deviation 0.97 |
| BIAsp 30 BID | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -1.73 Percent (%) glycosylated haemoglobin | Standard Deviation 0.93 |
Secondary
Change From Baseline in Body Weight
Change from baseline in body weight after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: The safety analysis set included all subjects who received at least one dose of the investigational product or its comparator. Missing data were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp BID | Change From Baseline in Body Weight | 2.8 kg | Standard Deviation 4.1 |
| BIAsp 30 BID | Change From Baseline in Body Weight | 2.0 kg | Standard Deviation 4.3 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Change from baseline in fasting plasma glucose (FPG) after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: The full analysis set (FAS) included all randomised subjects. Missing data were imputed using LOCF. At baseline 195 subjects each in IDegAsp BID and BIAsp 30 BID treatment group were analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp BID | Change From Baseline in Fasting Plasma Glucose (FPG) | -4.44 mmol/L | Standard Deviation 2.97 |
| BIAsp 30 BID | Change From Baseline in Fasting Plasma Glucose (FPG) | -3.03 mmol/L | Standard Deviation 2.9 |
Secondary
Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes
The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes, which is presented here. 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: Onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product
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 BID | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | 553 episodes |
| BIAsp 30 BID | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | 1221 episodes |
Secondary
Number of Treatment Emergent AEs (Adverse Events)
A Treatment Emergent Adverse Event (TEAE) was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. Severity was assessed by investigator.
Time frame: Onset on or after the first day of exposure to investigational product and no later than 7 days after exposure to investigational product
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 BID | Number of Treatment Emergent AEs (Adverse Events) | Serious | 20 events |
| IDegAsp BID | Number of Treatment Emergent AEs (Adverse Events) | Moderate | 45 events |
| IDegAsp BID | Number of Treatment Emergent AEs (Adverse Events) | Events | 197 events |
| IDegAsp BID | Number of Treatment Emergent AEs (Adverse Events) | Mild | 139 events |
| IDegAsp BID | Number of Treatment Emergent AEs (Adverse Events) | Severe | 13 events |
| IDegAsp BID | Number of Treatment Emergent AEs (Adverse Events) | Fatal | 2 events |
| BIAsp 30 BID | Number of Treatment Emergent AEs (Adverse Events) | Severe | 8 events |
| BIAsp 30 BID | Number of Treatment Emergent AEs (Adverse Events) | Events | 137 events |
| BIAsp 30 BID | Number of Treatment Emergent AEs (Adverse Events) | Serious | 12 events |
| BIAsp 30 BID | Number of Treatment Emergent AEs (Adverse Events) | Fatal | 2 events |
| BIAsp 30 BID | Number of Treatment Emergent AEs (Adverse Events) | Moderate | 27 events |
| BIAsp 30 BID | Number of Treatment Emergent AEs (Adverse Events) | Mild | 102 events |
Secondary
Number of Treatment Emergent Nocturnal (00:01-05:59 am) Severe or Minor Hypoglycaemic Episodes
The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes, which is presented here. 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 am.
Time frame: Onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product
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 BID | Number of Treatment Emergent Nocturnal (00:01-05:59 am) Severe or Minor Hypoglycaemic Episodes | 60 episodes |
| BIAsp 30 BID | Number of Treatment Emergent Nocturnal (00:01-05:59 am) Severe or Minor Hypoglycaemic Episodes | 260 episodes |
Secondary
Responder for HbA1c (Below 7.0%) Without Severe and Minor Treatment Emergent Hypoglycaemic Episodes During the Last 12 Weeks of Treatment Including Only Subjects Exposed for at Least 12 Weeks
Responder for HbA1c (\<7.0%) without severe and minor treatment emergent hypoglycaemic episodes during the last 12 weeks of treatment. Severe + minor hypoglycaemic episodes = confirmed hypoglycaemic episodes. Severe hypoglycaemic episodes: requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes: able to treat her/himself and plasma glucose below 3.1 mmol/L.
Time frame: Week 26
Population: The full analysis set (FAS) included all randomised subjects. Missing data were imputed using LOCF. Data for 15 subjects were excluded, as only subjects exposed for at least 12 weeks were included in this measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp BID | Responder for HbA1c (Below 7.0%) Without Severe and Minor Treatment Emergent Hypoglycaemic Episodes During the Last 12 Weeks of Treatment Including Only Subjects Exposed for at Least 12 Weeks | 77 participants |
| BIAsp 30 BID | Responder for HbA1c (Below 7.0%) Without Severe and Minor Treatment Emergent Hypoglycaemic Episodes During the Last 12 Weeks of Treatment Including Only Subjects Exposed for at Least 12 Weeks | 59 participants |