Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia, Europe and Oceania. The aim of this clinical trial is to compare NN5401 (insulin degludec/insulin aspart) with biphasic insulin aspart 30 in subjects with type 2 diabetes.
Interventions
DRUGinsulin degludec/insulin aspart
Injected s.c. (under the skin) with the breakfast meal and main evening meal. The dose were individually adjusted. Subjects continued their pre-trial OADs (oral antidiabetic drug(s)) treatment of Metformin, the specific DPP-4 Inhibitor and Pioglitazone.
DRUGbiphasic insulin aspart 30
Injected s.c. (under the skin) with the breakfast meal and main evening meal. The dose were individually adjusted. Subjects continued their pre-trial OADs (oral antidiabetic drug(s)) treatment of Metformin, the specific DPP-4 Inhibitor and Pioglitazone.
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 (diagnosed clinically) for at least 6 months * Subjects on premixed human or analogue insulin or self-mixed insulin regimen, containing 20-40 % fast/rapid-acting component, once daily (OD) or twice daily (BID), with or without oral antidiabetic drugs) (OADs) (metformin, sulphonylurea (SU), glinides, alpha-glucosidase inhibitor, DPP-4 (dipeptidyl peptidase-4) inhibitor and pioglitazone), for at least 3 months before Visit 1 * HbA1c 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 other insulin regimens than those listed in key inclusion criterion no. 2 within 3 months * Treatment with rosiglitazone or glucagon-like peptide-1 (GLP-1) receptor agonists (exenatide, liraglutide) within 3 months prior to visit 1 * 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 * Uncontrolled treated/untreated severe hypertension (systolic blood pressure at least 180 millimetre (mm) mercury (Hg) and/or diastolic blood pressure at least 100 mmHg) * Pregnancy, breast-feeding, the intention of becoming pregnant or not using adequate contraceptive measures according to local requirements * Cancer and medical history of cancer (except basal cell skin cancer and squamous cell skin cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) | Week 0, Week 26 | Change from baseline in HbA1c after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) | Week 26 | Mean of SMPG after 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. |
| Rate of Confirmed Hypoglycaemic Episodes | Week 0 to Week 26 + 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 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 | 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. |
Countries
Australia, Denmark, Finland, India, Malaysia, Poland, Sweden, Taiwan, Thailand, Turkey (Türkiye)
Participant flow
Recruitment details
The trial was conducted at 50 sites in 10 countries: Australia (5 sites), Denmark (7 sites), Finland (5 sites), India (9 sites), Malaysia (3 sites), Poland (5 sites), Sweden (6 sites), Taiwan (3 sites), Thailand (3 sites), Turkey (4 sites). In addition, 1 site in Thailand screened but did not randomise any subjects.
Pre-assignment details
Between screening and randomisation, eligible subjects were to continue their usual pre-trial oral anti-diabetic drug (OAD) of metformin, pioglitazone and DPP-4 inhibitor.
Participants by arm
| Arm | Count |
|---|---|
| IDegAsp BID Insulin degludec/insulin aspart (IDegAsp) was given subcutaneously twice daily (BID) with or without Metformin, DPP-4 inhibitor, Pioglitazone. IDegAsp was given with the breakfast meal and main evening meal. | 224 |
| BIAsp 30 BID Biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously twice daily (BID) with or without Metformin, DPP-4 inhibitor, Pioglitazone. BIAsp 30 was given with the breakfast meal and main evening meal. | 222 |
| Total | 446 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 4 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Unclassified | 17 | 21 |
| Overall Study | Withdrawal Criteria | 4 | 6 |
Baseline characteristics
| Characteristic | IDegAsp BID | BIAsp 30 BID | Total |
|---|---|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 9.9 | 58.8 years STANDARD_DEVIATION 9.8 | 58.7 years STANDARD_DEVIATION 9.8 |
| Fasting plasma glucose (FPG) | 8.9 mmol/L STANDARD_DEVIATION 2.9 | 8.6 mmol/L STANDARD_DEVIATION 2.6 | 8.7 mmol/L STANDARD_DEVIATION 2.8 |
| Glycosylated haemoglobin (HbA1c) | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.4 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.4 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 |
| Sex: Female, Male Female | 95 Participants | 103 Participants | 198 Participants |
| Sex: Female, Male Male | 129 Participants | 119 Participants | 248 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 60 / 224 | 52 / 222 |
| serious Total, serious adverse events | 19 / 224 | 36 / 222 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c)
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 randomised in error, hence removed from the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp BID | Change in Glycosylated Haemoglobin (HbA1c) | -1.28 percentage of glycosylated haemoglobin | Standard Deviation 0.94 |
| BIAsp 30 BID | Change in Glycosylated Haemoglobin (HbA1c) | -1.30 percentage of glycosylated haemoglobin | Standard Deviation 0.97 |
Secondary
Mean of 9-point Self Measured Plasma Glucose Profile (SMPG)
Mean of SMPG after 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 randomised in error, hence removed from the FAS. For 24 subjects all 9-point SMPG values were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp BID | Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) | 7.0 mmol/L | Standard Deviation 1.6 |
| BIAsp 30 BID | Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) | 7.3 mmol/L | Standard Deviation 2.1 |
Secondary
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 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: 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 | Rate of Confirmed Hypoglycaemic Episodes | 972 Episodes/100 years of patient exposure |
| BIAsp 30 BID | Rate of Confirmed Hypoglycaemic Episodes | 1396 Episodes/100 years of patient exposure |
Secondary
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 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: 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 | Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 74 Episodes/100 years of patient exposure |
| BIAsp 30 BID | Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 253 Episodes/100 years of patient exposure |