Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Africa, Asia, Europe, Oceania and South America. This trial aims for a comparison of biphasic insulin aspart 30 once daily versus insulin glargine once daily all in combination with metformin and glimepiride in insulin naive subjects with type 2 diabetes.
Interventions
DRUGbiphasic insulin aspart
Treat-to-target dose titration scheme. The titration scheme is based on the previous 3 days fasting plasma glucose (FPG) measurements.
DRUGinsulin glargine
Treat-to-target dose titration scheme. The titration scheme is based on the previous 3 days fasting plasma glucose (FPG) measurements.
DRUGmetformin
Tablets, 2550 mcg. Administered once daily.
DRUGglimepiride
Tablets 2 mg. 4, 6 or 8 mg administered 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
* Type 2 diabetes * Treatment with OADs (Oral Anti-Diabetic Drugs) for more than 6 months * Ongoing stable treatment with metformin for at least 2 months * Ongoing stable treatment with minimum half maximal dose of any insulin secretagogue for at least 2 months * Insulin naive * HbA1c (glycosylated haemoglobin A1c) between 7.0% and 11.0% (inclusive of both values)
Exclusion criteria
* Metformin contraindication according to local practice * TZD (thiazolidinedione) treatment for the last 5 months before trial start * Systemic treatment with any corticosteroid 3 months before trial start * Any disease or condition which according to the Investigator would interfere with the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glycosylated Haemoglobin A1c (HbA1c) | After 26 weeks of treatment | Glycosylated Haemoglobin A1c measured in blood samples after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 9-point Self-measured Plasma Glucose Profiles | After 26 weeks of treatment | Glycaemic control measured by 9-point self-measured plasma glucose (SMPG) profiles. The 9 time points for self-measurement during the day were: Before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, before bedtime, at 2-4 AM, and before breakfast the following day. Hypoglycaemia episodes were defined as major or minor. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL. |
| Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | After 26 weeks of treatment | The number of subjects achieving the treatment target for glycosylated haemoglobin A1c after 26 weeks treatment. The treatment targets were: HbA1c \<= 6.5% of haemoglobin and HbA1c \< 7% of haemoglobin. |
| Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) | After 26 weeks of treatment | Subjects assessed the burden, efficacy, symptoms and overall score in the treatment satisfaction questionnaire, Diab MedSat (Diabetes Medication Satisfaction questionnaire). The scores were transformed to a 0-100 scale with higher scores indicating greater satisfaction. The score of the subscales was computed as the mean of the items in each subscale. |
| Number of Hypoglycaemic Episodes | Weeks 0-26 | Total number of hypoglycaemic episodes experienced in each treatment arm. Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL. Symptoms only if subject was able to treat her/himself and with either no plasma glucose or blood glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L or 56 mg/dL. |
| Number of Subjects Reporting Treatment Emergent Adverse Events | Weeks 0-26 | Number of subjects reporting treatment emergent adverse events during the trial (from week 0 to week 26). Adverse events were reported as treatment emergent if they occurred from the date of first insulin trial product administration up to and including the date of last insulin trial product administration. |
Countries
Argentina, Austria, Czechia, France, India, Malaysia, Mexico, Netherlands, Philippines, Poland, Romania, Serbia and Montenegro, South Africa, Spain, Sweden
Participant flow
Recruitment details
Subjects were enrolled 64 sites in 15 countries in Africa, Europe, Asia, North America and South America.
Pre-assignment details
A screening period of 1-2 weeks was followed by a run-in period of 4 weeks during which metformin was titrated to maximum 2550 mg and glimepiride to 4 mg, at the discretion of the investigator. Subjects who were already taking 4, 6 or 8 mg glimepiride continued on this dose. Doses were kept constant during the last week prior to randomisation.
Participants by arm
| Arm | Count |
|---|---|
| BIAsp 30 Biphasic insulin aspart 30 + metformin + glimepiride | 231 |
| Glargine Insulin glargine + metformin + glimepiride | 238 |
| Total | 469 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal lab value | 1 | 0 |
| Overall Study | Adverse Event | 5 | 4 |
| Overall Study | Contraindication metformin/glimepiride | 1 | 0 |
| Overall Study | Hypoglycaemic Episodes | 1 | 1 |
| Overall Study | Incorrectly Randomised | 4 | 3 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Protocol Violation | 3 | 3 |
| Overall Study | Use of Corticosteroid | 1 | 0 |
| Overall Study | Use of lipid lowering drug | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
| Overall Study | Withdrawal Criteria | 3 | 4 |
Baseline characteristics
| Characteristic | Glargine | Total | BIAsp 30 |
|---|---|---|---|
| Age, Continuous | 56.1 years STANDARD_DEVIATION 10 | 56.0 years STANDARD_DEVIATION 9.9 | 55.9 years STANDARD_DEVIATION 9.7 |
| BMI | 29.1 kg/m^2 STANDARD_DEVIATION 4.6 | 29.1 kg/m^2 STANDARD_DEVIATION 4.6 | 29.0 kg/m^2 STANDARD_DEVIATION 4.6 |
| Diabetes duration | 9.5 years STANDARD_DEVIATION 6.1 | 9.3 years STANDARD_DEVIATION 6 | 9.1 years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants | 75 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 196 Participants | 388 Participants | 192 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants |
| Gender Female | 140 Participants | 263 Participants | 123 Participants |
| Gender Male | 98 Participants | 206 Participants | 108 Participants |
| HbA1c | 9.0 percentage of total haemoglobin STANDARD_DEVIATION 1.1 | 9.0 percentage of total haemoglobin STANDARD_DEVIATION 1.1 | 8.9 percentage of total haemoglobin STANDARD_DEVIATION 1 |
| Race (NIH/OMB) American Indian or Alaska Native | 11 Participants | 24 Participants | 13 Participants |
| Race (NIH/OMB) Asian | 79 Participants | 155 Participants | 76 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 17 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 9 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) White | 133 Participants | 258 Participants | 125 Participants |
| Weight | 77.3 kg STANDARD_DEVIATION 15.4 | 77.4 kg STANDARD_DEVIATION 15 | 77.5 kg STANDARD_DEVIATION 14.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 56 / 231 | 63 / 238 |
| serious Total, serious adverse events | 13 / 231 | 10 / 238 |
Outcome results
Primary
Glycosylated Haemoglobin A1c (HbA1c)
Glycosylated Haemoglobin A1c measured in blood samples after 26 weeks of treatment.
Time frame: After 26 weeks of treatment
Population: Intention to Treat (Last Observation Carried Forward) population. All randomised subjects exposed to trial drug, and who had at least a baseline HbA1c measurement and at least one post randomisation HbA1c measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Glycosylated Haemoglobin A1c (HbA1c) | 7.08 percentage of total haemoglobin | Standard Deviation 0.07 |
| Glargine | Glycosylated Haemoglobin A1c (HbA1c) | 7.23 percentage of total haemoglobin | Standard Deviation 0.07 |
Comparison: HbA1c was compared between the treatment groups by fitting a linear regression model (ANCOVA) with treatment and country as factors and the baseline values as a continuous covariate. Mean and SE are estimated from the model.p-value: 0.02995% CI: [-0.3, -0.02]Regression, Linear
Secondary
9-point Self-measured Plasma Glucose Profiles
Glycaemic control measured by 9-point self-measured plasma glucose (SMPG) profiles. The 9 time points for self-measurement during the day were: Before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, before bedtime, at 2-4 AM, and before breakfast the following day. Hypoglycaemia episodes were defined as major or minor. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL.
Time frame: After 26 weeks of treatment
Population: Intention to Treat, Last Observation Carried Forward population. All randomised subjects exposed to trial drug, and who had at least a baseline HbA1c measurement and at least one post randomisation HbA1c measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 30 | 9-point Self-measured Plasma Glucose Profiles | Before dinner | 7.90 mmol/L | Standard Error 0.18 |
| BIAsp 30 | 9-point Self-measured Plasma Glucose Profiles | 2 hours after dinner | 8.66 mmol/L | Standard Error 0.19 |
| BIAsp 30 | 9-point Self-measured Plasma Glucose Profiles | Before bedtime | 7.77 mmol/L | Standard Error 0.18 |
| BIAsp 30 | 9-point Self-measured Plasma Glucose Profiles | 02:00-04:00 AM | 6.56 mmol/L | Standard Error 0.14 |
| BIAsp 30 | 9-point Self-measured Plasma Glucose Profiles | Before breakfast following day | 6.65 mmol/L | Standard Error 0.12 |
| BIAsp 30 | 9-point Self-measured Plasma Glucose Profiles | Before breakfast | 6.73 mmol/L | Standard Error 0.12 |
| BIAsp 30 | 9-point Self-measured Plasma Glucose Profiles | 2 hours after breakfast | 9.40 mmol/L | Standard Error 0.2 |
| BIAsp 30 | 9-point Self-measured Plasma Glucose Profiles | Before lunch | 7.24 mmol/L | Standard Error 0.18 |
| BIAsp 30 | 9-point Self-measured Plasma Glucose Profiles | 2 hours after lunch | 8.90 mmol/L | Standard Error 0.2 |
| Glargine | 9-point Self-measured Plasma Glucose Profiles | Before lunch | 7.28 mmol/L | Standard Error 0.18 |
| Glargine | 9-point Self-measured Plasma Glucose Profiles | Before dinner | 7.80 mmol/L | Standard Error 0.18 |
| Glargine | 9-point Self-measured Plasma Glucose Profiles | Before breakfast | 6.56 mmol/L | Standard Error 0.12 |
| Glargine | 9-point Self-measured Plasma Glucose Profiles | 2 hours after dinner | 9.18 mmol/L | Standard Error 0.19 |
| Glargine | 9-point Self-measured Plasma Glucose Profiles | Before breakfast following day | 6.40 mmol/L | Standard Error 0.12 |
| Glargine | 9-point Self-measured Plasma Glucose Profiles | Before bedtime | 8.54 mmol/L | Standard Error 0.18 |
| Glargine | 9-point Self-measured Plasma Glucose Profiles | 2 hours after breakfast | 9.07 mmol/L | Standard Error 0.2 |
| Glargine | 9-point Self-measured Plasma Glucose Profiles | 02:00-04:00 AM | 6.69 mmol/L | Standard Error 0.14 |
| Glargine | 9-point Self-measured Plasma Glucose Profiles | 2 hours after lunch | 8.98 mmol/L | Standard Error 0.2 |
Comparison: The profiles were compared between the treatment groups by fitting a repeated measures mixed model including treatment, time, the treatment-by-time interaction and country as fixed effects, and subject as random effect.p-value: 0.0059Mixed Models Analysis
Secondary
Number of Hypoglycaemic Episodes
Total number of hypoglycaemic episodes experienced in each treatment arm. Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL. Symptoms only if subject was able to treat her/himself and with either no plasma glucose or blood glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L or 56 mg/dL.
Time frame: Weeks 0-26
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 30 | Number of Hypoglycaemic Episodes | Minor | 443 events |
| BIAsp 30 | Number of Hypoglycaemic Episodes | Symptom only | 265 events |
| BIAsp 30 | Number of Hypoglycaemic Episodes | Major | 3 events |
| BIAsp 30 | Number of Hypoglycaemic Episodes | Unclassified | 1 events |
| Glargine | Number of Hypoglycaemic Episodes | Unclassified | 0 events |
| Glargine | Number of Hypoglycaemic Episodes | Minor | 318 events |
| Glargine | Number of Hypoglycaemic Episodes | Major | 3 events |
| Glargine | Number of Hypoglycaemic Episodes | Symptom only | 224 events |
Secondary
Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c)
The number of subjects achieving the treatment target for glycosylated haemoglobin A1c after 26 weeks treatment. The treatment targets were: HbA1c \<= 6.5% of haemoglobin and HbA1c \< 7% of haemoglobin.
Time frame: After 26 weeks of treatment
Population: Intention to Treat, Last Observation Carried Forward population. All randomised subjects exposed to trial drug, and who had at least a baseline HbA1c measurement and at least one post randomisation HbA1c measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 30 | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c <= 6.5% of haemoglobin | 54 participants |
| BIAsp 30 | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c < 7.0% of haemoglobin | 101 participants |
| BIAsp 30 | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | Reduction > 1% point from baseline | 134 participants |
| BIAsp 30 | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c < 7% no nocturnal hypoglycemia | 82 participants |
| BIAsp 30 | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c < 7%, no daytime hypoglycemia | 52 participants |
| BIAsp 30 | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c < 7%, no hypoglycemia | 45 participants |
| Glargine | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c < 7%, no daytime hypoglycemia | 50 participants |
| Glargine | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c <= 6.5% of haemoglobin | 60 participants |
| Glargine | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c < 7% no nocturnal hypoglycemia | 92 participants |
| Glargine | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c < 7.0% of haemoglobin | 106 participants |
| Glargine | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | HbA1c < 7%, no hypoglycemia | 45 participants |
| Glargine | Number of Subjects Achieving the Treatment Target for Glycosylated Haemoglobin A1c (HbA1c) | Reduction > 1% point from baseline | 132 participants |
95% CI: [0.57, 1.47]
95% CI: [0.67, 1.54]
95% CI: [0.72, 1.77]
95% CI: [0.59, 1.38]
95% CI: [0.74, 1.87]
95% CI: [0.69, 1.82]
Secondary
Number of Subjects Reporting Treatment Emergent Adverse Events
Number of subjects reporting treatment emergent adverse events during the trial (from week 0 to week 26). Adverse events were reported as treatment emergent if they occurred from the date of first insulin trial product administration up to and including the date of last insulin trial product administration.
Time frame: Weeks 0-26
Population: The safety analysis population consists of all subjects exposed to trial products.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIAsp 30 | Number of Subjects Reporting Treatment Emergent Adverse Events | 117 participants |
| Glargine | Number of Subjects Reporting Treatment Emergent Adverse Events | 115 participants |
Secondary
Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat)
Subjects assessed the burden, efficacy, symptoms and overall score in the treatment satisfaction questionnaire, Diab MedSat (Diabetes Medication Satisfaction questionnaire). The scores were transformed to a 0-100 scale with higher scores indicating greater satisfaction. The score of the subscales was computed as the mean of the items in each subscale.
Time frame: After 26 weeks of treatment
Population: Intention to Treat, Last Observation Carried Forward population. All randomised subjects exposed to trial drug, and who had at least a baseline HbA1c measurement and at least one post randomisation HbA1c measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 30 | Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) | Overall Score | 76.53 scores on a scale | Standard Error 1.04 |
| BIAsp 30 | Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) | Efficacy Score | 73.25 scores on a scale | Standard Error 1.57 |
| BIAsp 30 | Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) | Burden Score | 83.10 scores on a scale | Standard Error 1.13 |
| BIAsp 30 | Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) | Symptoms Score | 72.42 scores on a scale | Standard Error 1.29 |
| Glargine | Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) | Burden Score | 83.06 scores on a scale | Standard Error 1.16 |
| Glargine | Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) | Overall Score | 76.64 scores on a scale | Standard Error 1.05 |
| Glargine | Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) | Symptoms Score | 72.81 scores on a scale | Standard Error 1.29 |
| Glargine | Treatment Satisfaction as Measured by the Diabetes Medication Satisfaction Questionnaire (Diab MedSat) | Efficacy Score | 73.47 scores on a scale | Standard Error 1.57 |
Comparison: The Diab MedSat measure was scored as an overall score as well as three subscale scores. The scores were transformed to a 0-100 scale with higher scores indicating greater satisfaction. The score of the subscales was computed as the mean of the items in each subscale. The overall score is the mean of all three subscales.95% CI: [-2.4, 2.48]
Comparison: The Diab MedSat measure was scored as an overall score as well as three subscale scores. The scores were transformed to a 0-100 scale with higher scores indicating greater satisfaction. The score of the subscales was computed as the mean of the items in each subscale. The overall score is the mean of all three subscales.95% CI: [-3.56, 3.11]
Comparison: The Diab MedSat measure was scored as an overall score as well as three subscale scores. The scores were transformed to a 0-100 scale with higher scores indicating greater satisfaction. The score of the subscales was computed as the mean of the items in each subscale. The overall score is the mean of all three subscales.95% CI: [-3.14, 2.35]
Comparison: Diab MedSat measure was scored as an overall score as well as three subscale scores, and transformed to a 0-100 scale with higher scores indicating greater satisfaction. The score of the subscales was computed as the mean of the items in each subscale. The overall score is the mean of all three subscales.95% CI: [-2.36, 2.14]Regression, Linear