Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe, Africa and the United States of America (USA). The aim of this trial is to compare the safety and efficacy of two different insulin treatments, the basic and the advanced treatment in type 2 diabetes.
Interventions
DRUGinsulin detemir
Treat-to-target dose titration scheme (individually adjusted dose) for a once daily injection s.c. (under the skin)
DRUGinsulin aspart
Administered 1 - 3 times daily, at largest prandial increment, injection s.c. (under the skin)
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 for more than 6 months * HbA1c (glycosylated haemoglobin A1c) between 7.5 % and 10.0% at trial initiation (screening) * BMI (Body Mass Index) less than 40 kg/m2 * Basal insulin treatment for at least 3 months (NPH once or twice daily, insulin glargine or detemir once daily) * Treatment with one to 3 OADs
Exclusion criteria
* Known or suspected allergy to trial products or related products * Women who are pregnant, are breast-feeding or intend to become pregnant within the next 48 weeks * Previous participation in any trial including this for the last 6 months * Use of more than 1 U/kg of basal insulin daily at trial initiation (screening)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glycosylated Haemoglobin A1c (HbA1c) | week 36 | Analysed for the full analysis set. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hypoglycaemic Episodes | Weeks 0-36 | Number of hypoglycaemic episodes from Week 0 to Week 36, defined as major, minor or symptoms only. Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L (56 mg/dL). Symptoms only if able to treat her/himself and no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L. |
| Biochemistry: Serum Alanine Aminotransferase | week 36 | Alanine aminotransferase was measured in serum at week 36. Serum samples were analysed at a central laboratory. |
| Haematology: Haemoglobin Measured in Blood | week 36 | Haemoglobin was measured in blood samples at week 36. Blood samples were analysed at a central laboratory. |
| Cardiovascular Risk Marker: High-sensitivity C-reactive Peptide | week 36 | High-sensitivity C-reactive peptide was measured in serum at week 36. Serum samples were analysed at a central laboratory. |
Countries
Denmark, Finland, France, Netherlands, Norway, Russia, Serbia and Montenegro, South Africa, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
A total of 67 centres in 12 countries participated: Denmark (1), Finland (6), France (5), Netherlands (6), Norway (5), Russian Federation (4), Serbia (2), South Africa (3), Spain (5), Sweden (3), United Kingdom (7), United States of America (20)
Pre-assignment details
Eligible subjects were included in a 12-weeks forced titration period with insulin detemir as add-on to current oral anti-diabetic drug (OAD) treatment. Those subjects who did not meet the HbA1c target below 7% were then randomised to one of the two treatment regimens. Any use of sulphonylurea was discontinued at the time of randomisation.
Participants by arm
| Arm | Count |
|---|---|
| Advanced Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the meals with the largest prandial increments and individually adjusted insulin aspart based mainly on postmeal SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively. | 146 |
| Basic Insulin detemir once daily + oral anti-diabetic drugs (OADs) with addition of meal-time insulin aspart stepwise (1-2-3) at the largest meals and individually adjusted insulin aspart based mainly on pre-meal and bedtime SMPG (self monitored plasma glucose). The stepwise addition occurred if the treatment target of HbA1c below 7.0% was not reached after 12, 24 and 36 weeks, respectively. | 150 |
| Total | 296 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Lack of Efficacy | 6 | 7 |
| Overall Study | Protocol Violation | 8 | 4 |
| Overall Study | Unclassified | 8 | 7 |
| Overall Study | Withdrawal criteria | 3 | 3 |
Baseline characteristics
| Characteristic | Total | Advanced | Basic |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 57 Participants | 29 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 239 Participants | 117 Participants | 122 Participants |
| Age, Continuous | 58.3 years STANDARD_DEVIATION 8.4 | 58.3 years STANDARD_DEVIATION 8.29 | 58.3 years STANDARD_DEVIATION 8.54 |
| BMI (Body Mass Index) | 31.32 kg/m^2 STANDARD_DEVIATION 4.6 | 31.26 kg/m^2 STANDARD_DEVIATION 4.26 | 31.38 kg/m^2 STANDARD_DEVIATION 4.92 |
| Body weight | 88.4 kg STANDARD_DEVIATION 16 | 88.8 kg STANDARD_DEVIATION 15.8 | 88.0 kg STANDARD_DEVIATION 16.3 |
| Diabetes history | 12.25 years STANDARD_DEVIATION 6.35 | 11.82 years STANDARD_DEVIATION 5.99 | 12.68 years STANDARD_DEVIATION 6.68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 60 Participants | 26 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 211 Participants | 108 Participants | 103 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 25 Participants | 12 Participants | 13 Participants |
| HbA1c (glycosylated haemoglobin A1c) | 8.78 percentage (%) of total haemoglobin STANDARD_DEVIATION 1.07 | 8.89 percentage (%) of total haemoglobin STANDARD_DEVIATION 1.16 | 8.67 percentage (%) of total haemoglobin STANDARD_DEVIATION 0.97 |
| Height | 1.68 meter STANDARD_DEVIATION 0.1 | 1.68 meter STANDARD_DEVIATION 0.1 | 1.67 meter STANDARD_DEVIATION 0.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 8 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 25 Participants | 12 Participants | 13 Participants |
| Race (NIH/OMB) White | 242 Participants | 120 Participants | 122 Participants |
| Sex: Female, Male Female | 137 Participants | 70 Participants | 67 Participants |
| Sex: Female, Male Male | 159 Participants | 76 Participants | 83 Participants |
| Stratification Metformin alone | 126 participants | 62 participants | 64 participants |
| Stratification Metformin + other OAD | 170 participants | 84 participants | 86 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 146 | 58 / 150 |
| serious Total, serious adverse events | 4 / 146 | 8 / 150 |
Outcome results
Primary
Glycosylated Haemoglobin A1c (HbA1c)
Analysed for the full analysis set.
Time frame: week 36
Population: Full analysis set (FAS) is all randomised subjects exposed to at least one dose of trial products.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Advanced | Glycosylated Haemoglobin A1c (HbA1c) | 7.67 percentage (%) of total haemoglobin | Standard Error 0.09 |
| Basic | Glycosylated Haemoglobin A1c (HbA1c) | 7.61 percentage (%) of total haemoglobin | Standard Error 0.08 |
Comparison: Equivalence analysis with a null hypothesis stating that there is a difference between Advanced and Basic treatment groups of more than 0.4%.p-value: 0.60695% CI: [-0.17, 0.29]ANCOVA
Primary
Glycosylated Haemoglobin A1c (HbA1c)
Measured for the Per Protocol analysis set.
Time frame: week 36
Population: Per Protocol analysis set: All exposed subjects who completed the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Advanced | Glycosylated Haemoglobin A1c (HbA1c) | 7.55 percentage (%) of total haemoglobin | Standard Error 0.09 |
| Basic | Glycosylated Haemoglobin A1c (HbA1c) | 7.52 percentage (%) of total haemoglobin | Standard Error 0.08 |
Comparison: Equivalence analysis with a null hypothesis stating that there is a difference between Advanced and Basic treatment groups of more than 0.4%.p-value: 0.81695% CI: [-0.21, 0.26]ANCOVA
Secondary
Biochemistry: Serum Alanine Aminotransferase
Alanine aminotransferase was measured in serum at week 36. Serum samples were analysed at a central laboratory.
Time frame: week 36
Population: Safety Analysis Set is all randomised subjects exposed to at least one dose of trial products.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Advanced | Biochemistry: Serum Alanine Aminotransferase | 30.09 U/L | Standard Deviation 18.54 |
| Basic | Biochemistry: Serum Alanine Aminotransferase | 27.04 U/L | Standard Deviation 14.64 |
Secondary
Cardiovascular Risk Marker: High-sensitivity C-reactive Peptide
High-sensitivity C-reactive peptide was measured in serum at week 36. Serum samples were analysed at a central laboratory.
Time frame: week 36
Population: Safety Analysis Set is all randomised subjects exposed to at least one dose of trial products.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Advanced | Cardiovascular Risk Marker: High-sensitivity C-reactive Peptide | 3.76 mg/L | Standard Deviation 3.46 |
| Basic | Cardiovascular Risk Marker: High-sensitivity C-reactive Peptide | 4.67 mg/L | Standard Deviation 6.86 |
Secondary
Haematology: Haemoglobin Measured in Blood
Haemoglobin was measured in blood samples at week 36. Blood samples were analysed at a central laboratory.
Time frame: week 36
Population: Safety Analysis Set is all randomised subjects exposed to at least one dose of trial products.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Advanced | Haematology: Haemoglobin Measured in Blood | 8.57 mmol/L | Standard Deviation 0.87 |
| Basic | Haematology: Haemoglobin Measured in Blood | 8.58 mmol/L | Standard Deviation 0.95 |
Secondary
Hypoglycaemic Episodes
Number of hypoglycaemic episodes from Week 0 to Week 36, defined as major, minor or symptoms only. Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L (56 mg/dL). Symptoms only if able to treat her/himself and no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L.
Time frame: Weeks 0-36
Population: Safety Analysis Set is all randomised subjects exposed to at least one dose of trial products.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Advanced | Hypoglycaemic Episodes | Major | 1 episodes |
| Advanced | Hypoglycaemic Episodes | Minor | 531 episodes |
| Advanced | Hypoglycaemic Episodes | Symptoms Only | 283 episodes |
| Basic | Hypoglycaemic Episodes | Major | 4 episodes |
| Basic | Hypoglycaemic Episodes | Minor | 567 episodes |
| Basic | Hypoglycaemic Episodes | Symptoms Only | 344 episodes |