Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted globally. The aim of this trial is to compare stepwise insulin intensification of biphasic insulin aspart (BIAsp) 30 and basal-bolus therapy with insulin glargine and insulin aspart in insulin naïve type 2 diabetic patients inadequately controlled on oral anti-diabetic therapy.
Interventions
DRUGbiphasic insulin aspart 30
Injected s.c./subcutaneously once daily with the largest meal Subjects should continue their pre-trial metformin and sulfonylurea dosages all throughout the trial while other oral antidiabetic drugs will be discontinued.
DRUGinsulin glargine
Injected s.c./subcutaneously once daily at the same time every day, with the possibility of treatment intensification with insulin aspart (Basal-bolus arm) Subjects should continue their pre-trial metformin and sulfonylurea dosages all throughout the trial while other oral antidiabetic drugs will be discontinued.
DRUGinsulin aspart
Injected s.c./subcutaneously once daily.
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 procedures that are carried out as part of the trial, including activities to determine suitability for the trial * Male or female, age at least 18 years at the time of signing informed consent * Type 2 diabetes subjects clinically diagnosed at least 6 months prior to screening * Treatment with stable daily dose (for at least 90 days prior to screening) of: - Metformin (equal or above 1000 mg or maximum tolerated dose documented in the patient medical record) and - Sulfonylurea - and willing to discontinue any other oral antidiabetic drugs containing insulin secretagogues, DPP4i (dipeptidyl peptidase-4 inhibitor), SGLT2 (sodium glucose co-transporter 2), colesevelam, bromocriptin and/or combination products at randomisation * Insulin-naïve. Short term insulin treatment for acute illnesses for a total of 14 days or less is allowed as is prior insulin treatment for gestational diabetes * HbA1c (glycosylated haemoglobin) 7.0-9.5 % (both inclusive) analysed by central laboratory * Willing to consume 3 main meals daily (morning, mid-day and evening) throughout the entire trial. The definition for 'main meal' will be according to the investigator's discretion
Exclusion criteria
* Anticipated initiation or change in concomitant medications known to affect weight or glucose metabolism, in excess of 14 days (i.e. sibutramine, orlistat, thyroid hormones, systemic corticosteroids and other weight loss/modifying agents) * Impaired liver function, defined as ALT (alanine aminotransferase) at least 2.5 times upper limit of normal (central laboratory value measured at screening visit) * Inadequately treated high blood pressure defined as Class 2 hypertension or higher (i.e. systolic blood pressure equal to or above 160 mm Hg or diastolic equal to or above 100 mm Hg) in accordance with the National High Blood Pressure Education Program, 7th Joint National Committee1 and ESH/ESC 2013 Guidelines2 * Within the past 180 days prior to randomisation, any of the following: Myocardial Infarction, stroke or hospitalization for unstable angina and /or transient ischemic attack
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (Glycosylated Haemoglobin) | Week 0, week 32 | Change in HbA1c from baseline (week 0) to week 32. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes | After 32 weeks of treatment (yes/no) | Percentage of subjects with HbA1c below 7.0% after 32 weeks of randomised treatment without treatment emergent severe hypoglycaemic episodes during the last 12 weeks of treatment. Subjects withdrawn before 32 weeks were handled as non-responders. Severe hypoglycaemic episode was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose (PG) concentrations may not be available during an event, but neurological recovery following the return of PG to normal is considered sufficient evidence that the event was induced by a low PG concentration. |
| Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) and the Novo Nordisk Definitions | Weeks 0-32 | Hypoglycaemic episodes were classified as severe, Asymptomatic, Documented symptomatic, Pseudo, and Probable symptomatic as per ADA classification. As symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L, (56 mg/dL) Novo Nordisk classification included hypoglycaemia with plasma glucose (PG) levels below 3.1 mmol/L (56 mg/dL) in the definition of blood glucose confirmed hypoglycaemia. Hence, Novo Nordisk classification included following types of hypoglycaemia in addition to ADA classification: Severe hypoglycaemia, Symptomatic blood glucose confirmed hypoglycaemia, Asymptomatic blood glucose confirmed hypoglycaemia, Severe or blood glucose confirmed symptomatic hypoglycaemia, Blood glucose confirmed hypoglycaemia, and Severe or blood glucose confirmed hypoglycaemia. Reported data represents total of all hypoglycaemic episodes. |
| Total Daily Insulin Dose | Weeks 0-32 | Total daily insulin dose in the basal bolus treatment group and in BIAsp 30 treatment group at each week of each treatment. |
Countries
Australia, Bulgaria, Hungary, India, Serbia, South Korea, Thailand, Turkey (Türkiye), United Arab Emirates
Participant flow
Recruitment details
The trial was conducted at 41 sites in 9 countries, as follows: Australia: 4 sites; Bulgaria: 5 sites; Hungary: 3 sites; India: 7 sites; Korea, Republic of: 4 sites; Serbia: 5 sites; Thailand: 4 sites; Turkey: 5 sites; United Arab Emirates: 4 sites.
Participants by arm
| Arm | Count |
|---|---|
| BIAsp 30 Subjects received s.c. injection of BIAsp 30 (a mixture of soluble IAsp 30% and protaminated IAsp 70%) during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started treatment with 1 daily injection of BIAsp 30 (starting dose 12 unit) with the largest meal. Insulin titration: Subjects underwent weekly insulin dose titration during entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in stepwise manner by adding an additional injection of BIAsp 30 depending on whether subjects achieved the pre-defined glycaemic target (HbA1c \<7.0%). Subjects had the possibility of receiving up to 3 daily injections of BIAsp 30. Subjects continued pre-trial treatment with metformin and SU throughout the trial. | 168 |
| Basal-bolus Subjects received s.c. injections of IGlar during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started with 1 daily injection of IGlar (administrated at same point of time every day) with starting dose of 10 units. Insulin titration: Subjects underwent a weekly insulin dose titration during the entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in a stepwise manner by adding an additional injection of IAsp depending on whether subjects achieved the pre-defined glycaemic target (HbA1c \<7.0%). Subjects had the possibility of receiving 1 daily injection of IGlar plus up to 3 daily injections of IAsp. Subjects continued their pre-trial treatment with metformin and SU throughout the trial. | 167 |
| Total | 335 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 7 | 4 |
| Overall Study | Unclassified | 4 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 4 |
Baseline characteristics
| Characteristic | BIAsp 30 | Basal-bolus | Total |
|---|---|---|---|
| Age, Continuous | 56.6 Years STANDARD_DEVIATION 10.4 | 56.5 Years STANDARD_DEVIATION 10.1 | 56.6 Years STANDARD_DEVIATION 10.2 |
| HbA1c | 8.31 Percentage of HbA1c STANDARD_DEVIATION 0.73 | 8.23 Percentage of HbA1c STANDARD_DEVIATION 0.69 | 8.27 Percentage of HbA1c STANDARD_DEVIATION 0.71 |
| Sex: Female, Male Female | 79 Participants | 90 Participants | 169 Participants |
| Sex: Female, Male Male | 89 Participants | 77 Participants | 166 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 166 | 40 / 166 |
| serious Total, serious adverse events | 14 / 166 | 12 / 166 |
Outcome results
Primary
Change in HbA1c (Glycosylated Haemoglobin)
Change in HbA1c from baseline (week 0) to week 32.
Time frame: Week 0, week 32
Population: Full analysis set. Week 32 data are presented after application of Last observation carried forward; 164 subjects contributed in each arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Change in HbA1c (Glycosylated Haemoglobin) | -1.16 Percentage of HbA1c | Standard Deviation 0.98 |
| Basal-bolus | Change in HbA1c (Glycosylated Haemoglobin) | -1.30 Percentage of HbA1c | Standard Deviation 0.9 |
Comparison: Analysis was performed using mixed model repeated measurements including treatment, region, and strata as fixed effects, HbA1c at baseline as covariate, interactions between all fixed effects and visit and using an unstructured residual covariance matrix.p-value: 0.043595% CI: [0.01, 0.36]Mixed Models Analysis
Secondary
HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes
Percentage of subjects with HbA1c below 7.0% after 32 weeks of randomised treatment without treatment emergent severe hypoglycaemic episodes during the last 12 weeks of treatment. Subjects withdrawn before 32 weeks were handled as non-responders. Severe hypoglycaemic episode was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose (PG) concentrations may not be available during an event, but neurological recovery following the return of PG to normal is considered sufficient evidence that the event was induced by a low PG concentration.
Time frame: After 32 weeks of treatment (yes/no)
Population: Full analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 30 | HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes | Yes | 42.3 Percentage of subjects |
| BIAsp 30 | HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes | No | 57.7 Percentage of subjects |
| Basal-bolus | HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes | Yes | 56.3 Percentage of subjects |
| Basal-bolus | HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes | No | 43.7 Percentage of subjects |
Secondary
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) and the Novo Nordisk Definitions
Hypoglycaemic episodes were classified as severe, Asymptomatic, Documented symptomatic, Pseudo, and Probable symptomatic as per ADA classification. As symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L, (56 mg/dL) Novo Nordisk classification included hypoglycaemia with plasma glucose (PG) levels below 3.1 mmol/L (56 mg/dL) in the definition of blood glucose confirmed hypoglycaemia. Hence, Novo Nordisk classification included following types of hypoglycaemia in addition to ADA classification: Severe hypoglycaemia, Symptomatic blood glucose confirmed hypoglycaemia, Asymptomatic blood glucose confirmed hypoglycaemia, Severe or blood glucose confirmed symptomatic hypoglycaemia, Blood glucose confirmed hypoglycaemia, and Severe or blood glucose confirmed hypoglycaemia. Reported data represents total of all hypoglycaemic episodes.
Time frame: Weeks 0-32
Population: The safety analysis set included all subjects receiving at least one dose of the investigational product or its comparator.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 30 | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) and the Novo Nordisk Definitions | ADA classification | 1650 Hypoglycaemic episodes |
| BIAsp 30 | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) and the Novo Nordisk Definitions | Novo Nordisk classification | 1650 Hypoglycaemic episodes |
| Basal-bolus | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) and the Novo Nordisk Definitions | ADA classification | 1841 Hypoglycaemic episodes |
| Basal-bolus | Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) and the Novo Nordisk Definitions | Novo Nordisk classification | 1841 Hypoglycaemic episodes |
Secondary
Total Daily Insulin Dose
Total daily insulin dose in the basal bolus treatment group and in BIAsp 30 treatment group at each week of each treatment.
Time frame: Weeks 0-32
Population: Safety analysis set. Number analysed=number of subjects with available data for individual timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 30 | Total Daily Insulin Dose | Week 8 | 0.308 U/kg | Standard Deviation 0.145 |
| BIAsp 30 | Total Daily Insulin Dose | Week 1 | 0.157 U/kg | Standard Deviation 0.038 |
| BIAsp 30 | Total Daily Insulin Dose | Week 17 | 0.528 U/kg | Standard Deviation 0.324 |
| BIAsp 30 | Total Daily Insulin Dose | Week 2 | 0.187 U/kg | Standard Deviation 0.053 |
| BIAsp 30 | Total Daily Insulin Dose | Week 13 | 0.456 U/kg | Standard Deviation 0.267 |
| BIAsp 30 | Total Daily Insulin Dose | Week 3 | 0.214 U/kg | Standard Deviation 0.07 |
| BIAsp 30 | Total Daily Insulin Dose | Week 18 | 0.546 U/kg | Standard Deviation 0.334 |
| BIAsp 30 | Total Daily Insulin Dose | Week 4 | 0.238 U/kg | Standard Deviation 0.088 |
| BIAsp 30 | Total Daily Insulin Dose | Week 11 | 0.421 U/kg | Standard Deviation 0.224 |
| BIAsp 30 | Total Daily Insulin Dose | Week 5 | 0.259 U/kg | Standard Deviation 0.102 |
| BIAsp 30 | Total Daily Insulin Dose | Week 19 | 0.557 U/kg | Standard Deviation 0.353 |
| BIAsp 30 | Total Daily Insulin Dose | Week 6 | 0.280 U/kg | Standard Deviation 0.114 |
| BIAsp 30 | Total Daily Insulin Dose | Week 14 | 0.472 U/kg | Standard Deviation 0.277 |
| BIAsp 30 | Total Daily Insulin Dose | Week 7 | 0.296 U/kg | Standard Deviation 0.131 |
| BIAsp 30 | Total Daily Insulin Dose | Week 24 | 0.615 U/kg | Standard Deviation 0.426 |
| BIAsp 30 | Total Daily Insulin Dose | Week 20 | 0.569 U/kg | Standard Deviation 0.367 |
| BIAsp 30 | Total Daily Insulin Dose | Week 25 | 0.628 U/kg | Standard Deviation 0.435 |
| BIAsp 30 | Total Daily Insulin Dose | Week 10 | 0.397 U/kg | Standard Deviation 0.199 |
| BIAsp 30 | Total Daily Insulin Dose | Week 26 | 0.643 U/kg | Standard Deviation 0.454 |
| BIAsp 30 | Total Daily Insulin Dose | Week 21 | 0.588 U/kg | Standard Deviation 0.387 |
| BIAsp 30 | Total Daily Insulin Dose | Week 27 | 0.661 U/kg | Standard Deviation 0.472 |
| BIAsp 30 | Total Daily Insulin Dose | Week 15 | 0.487 U/kg | Standard Deviation 0.295 |
| BIAsp 30 | Total Daily Insulin Dose | Week 28 | 0.671 U/kg | Standard Deviation 0.487 |
| BIAsp 30 | Total Daily Insulin Dose | Week 22 | 0.602 U/kg | Standard Deviation 0.401 |
| BIAsp 30 | Total Daily Insulin Dose | Week 29 | 0.688 U/kg | Standard Deviation 0.509 |
| BIAsp 30 | Total Daily Insulin Dose | Week 12 | 0.443 U/kg | Standard Deviation 0.245 |
| BIAsp 30 | Total Daily Insulin Dose | Week 30 | 0.692 U/kg | Standard Deviation 0.511 |
| BIAsp 30 | Total Daily Insulin Dose | Week 23 | 0.607 U/kg | Standard Deviation 0.411 |
| BIAsp 30 | Total Daily Insulin Dose | Week 31 | 0.703 U/kg | Standard Deviation 0.525 |
| BIAsp 30 | Total Daily Insulin Dose | Week 16 | 0.501 U/kg | Standard Deviation 0.308 |
| BIAsp 30 | Total Daily Insulin Dose | Week 32 | 0.700 U/kg | Standard Deviation 0.542 |
| BIAsp 30 | Total Daily Insulin Dose | Week 9 | 0.369 U/kg | Standard Deviation 0.172 |
| Basal-bolus | Total Daily Insulin Dose | Week 32 | 0.708 U/kg | Standard Deviation 0.537 |
| Basal-bolus | Total Daily Insulin Dose | Week 9 | 0.339 U/kg | Standard Deviation 0.137 |
| Basal-bolus | Total Daily Insulin Dose | Week 10 | 0.365 U/kg | Standard Deviation 0.16 |
| Basal-bolus | Total Daily Insulin Dose | Week 11 | 0.391 U/kg | Standard Deviation 0.182 |
| Basal-bolus | Total Daily Insulin Dose | Week 12 | 0.413 U/kg | Standard Deviation 0.202 |
| Basal-bolus | Total Daily Insulin Dose | Week 13 | 0.425 U/kg | Standard Deviation 0.214 |
| Basal-bolus | Total Daily Insulin Dose | Week 14 | 0.439 U/kg | Standard Deviation 0.228 |
| Basal-bolus | Total Daily Insulin Dose | Week 15 | 0.455 U/kg | Standard Deviation 0.237 |
| Basal-bolus | Total Daily Insulin Dose | Week 16 | 0.468 U/kg | Standard Deviation 0.248 |
| Basal-bolus | Total Daily Insulin Dose | Week 17 | 0.496 U/kg | Standard Deviation 0.27 |
| Basal-bolus | Total Daily Insulin Dose | Week 18 | 0.516 U/kg | Standard Deviation 0.294 |
| Basal-bolus | Total Daily Insulin Dose | Week 19 | 0.532 U/kg | Standard Deviation 0.316 |
| Basal-bolus | Total Daily Insulin Dose | Week 20 | 0.544 U/kg | Standard Deviation 0.32 |
| Basal-bolus | Total Daily Insulin Dose | Week 21 | 0.563 U/kg | Standard Deviation 0.347 |
| Basal-bolus | Total Daily Insulin Dose | Week 22 | 0.580 U/kg | Standard Deviation 0.359 |
| Basal-bolus | Total Daily Insulin Dose | Week 23 | 0.590 U/kg | Standard Deviation 0.373 |
| Basal-bolus | Total Daily Insulin Dose | Week 7 | 0.281 U/kg | Standard Deviation 0.11 |
| Basal-bolus | Total Daily Insulin Dose | Week 1 | 0.127 U/kg | Standard Deviation 0.026 |
| Basal-bolus | Total Daily Insulin Dose | Week 2 | 0.167 U/kg | Standard Deviation 0.042 |
| Basal-bolus | Total Daily Insulin Dose | Week 3 | 0.197 U/kg | Standard Deviation 0.061 |
| Basal-bolus | Total Daily Insulin Dose | Week 4 | 0.224 U/kg | Standard Deviation 0.076 |
| Basal-bolus | Total Daily Insulin Dose | Week 5 | 0.244 U/kg | Standard Deviation 0.088 |
| Basal-bolus | Total Daily Insulin Dose | Week 6 | 0.264 U/kg | Standard Deviation 0.1 |
| Basal-bolus | Total Daily Insulin Dose | Week 24 | 0.605 U/kg | Standard Deviation 0.386 |
| Basal-bolus | Total Daily Insulin Dose | Week 25 | 0.618 U/kg | Standard Deviation 0.398 |
| Basal-bolus | Total Daily Insulin Dose | Week 26 | 0.643 U/kg | Standard Deviation 0.434 |
| Basal-bolus | Total Daily Insulin Dose | Week 27 | 0.653 U/kg | Standard Deviation 0.452 |
| Basal-bolus | Total Daily Insulin Dose | Week 28 | 0.664 U/kg | Standard Deviation 0.466 |
| Basal-bolus | Total Daily Insulin Dose | Week 29 | 0.674 U/kg | Standard Deviation 0.484 |
| Basal-bolus | Total Daily Insulin Dose | Week 30 | 0.682 U/kg | Standard Deviation 0.497 |
| Basal-bolus | Total Daily Insulin Dose | Week 31 | 0.693 U/kg | Standard Deviation 0.515 |
| Basal-bolus | Total Daily Insulin Dose | Week 8 | 0.296 U/kg | Standard Deviation 0.119 |