Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia, Europe and North America. This trial aims for comparison of the effect on the glycemic control in subjects with type 2 diabetes of basal insulin analogue with one oral anti-diabetic drug (OAD) versus oral anti-diabetic drug alone.
Interventions
DRUGinsulin detemir
The detemir insulin dose is injected subcutaneously (under the skin) once daily in the evening and will be titrated (individually adjusted) weekly throughout the trial.
DRUGsitagliptin
The sitagliptin dose is 100 mg/ day and should be kept stable throughout the trial. Frequency of sitagliptin is once daily.
DRUGmetformin
Metformin treatment with at least 1000 mg/ day. Dose and dosing frequency should remain unchanged throughout the trial.
DRUGsulphonylurea
Sulphonylurea (SU) dose and dosing frequency should initially remain unchanged. In case of hypoglycaemia SU dose may be reduced at the discretion of the investigator.
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
* Diagnosed with type 2 diabetes for at least 6 months before trial start * Treatment with at least 1000 mg metformin per day for at least 3 months * Insulin-naive (short-term insulin treatment of up to 14 days is allowed) * DPP-4 (dipeptidyl peptidase-4) inhibitor naive * HbA1c (glycosylated haemoglobin A1c) between 7.5-10.0% by central laboratory analysis * BMI (Body Mass Index) lesser than or equal to 45.0 kg/m2 * Able and willing to take one subcutaneous injection every day * Able and willing to perform mandatory SMPG (self measured plasma glucose) measurements
Exclusion criteria
* Known or suspected allergy or intolerance to any of the trial products or related products * Severe hypertension * Treatment with thiazolidinedione (TZD) or GLP-1 (glucagon-like peptide-1) analogues within 2 months prior to trial start * Cardiac disease, within the last 12 months * Impaired hepatic function * Impaired renal function * Proliferative retinopathy or macular oedema requiring acute treatment * Female of childbearing potential * Known or suspected abuse of alcohol, narcotics or illicit substances
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| HbA1c (Glycosylated Haemoglobin A1c) | Week 26 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% Without Symptomatic Hypoglycaemia | Week 26 | Symptomatic hypoglycaemia is biochemically confirmed hypoglycaemia or major hypoglycaemia |
| Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% | Week 26 | — |
| Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% Without Symptomatic Hypoglycaemia | Week 26 | Symptomatic hypoglycaemia is biochemically confirmed hypoglycaemia or major hypoglycaemia |
| Change in BMI (Body Mass Index) | Week 0, Week 26 | — |
| Change in Body Weight | Week 0, Week 26 | — |
| Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% | Week 26 | — |
| Hypoglycemic Episodes | Weeks 0-26 | Overall: All episodes. Minor: Symptomatic, with PG \< 3.1 mmol/L. Symptoms only: Symptomatic with PG ≥ 3.1 mmol/L |
| Hypoglycemic Episodes: Day Time | Weeks 0-26 | Day time: Episodes between 6 pm and 11 am. Overall: All episodes. Minor: Symptomatic, with PG \< 3.1 mmol/L. Symptoms only: Symptomatic with PG ≥ 3.1 mmol/L |
| Hypoglycemic Episodes: Night Time | Weeks 0-26 | Night time: Episodes between 11 am and 6 pm. Overall: All episodes. Minor: Symptomatic, with PG \< 3.1 mmol/L. Symptoms only: Symptomatic with PG ≥ 3.1 mmol/L |
| Self-measured 9-point Plasma Glucose Profile | Week 26 | — |
| FPG (Fasting Plasma Glucose) | Week 26 | — |
Countries
Canada, Finland, France, Hungary, Slovakia, South Korea, Turkey (Türkiye), United States
Participant flow
Recruitment details
48 sites in 8 countries: Canada, Finland, France, Hungary, Slovakia, Republic of Korea, Turkey, and the United States of America (USA)
Pre-assignment details
Between screening and randomisation, eligible subjects were to continue their usual pre-trial oral anti-diabetic drug (OAD) dose and dosing frequency. Subjects on sulphonylurea (SU) treatment randomised to the insulin detemir group had their SU discontinued
Participants by arm
| Arm | Count |
|---|---|
| Comb Combination therapy of insulin detemir once daily plus sitagliptin added to subject's own pre-trial metformin treatment | 107 |
| Sita Monotherapy of sitagliptin once daily added to subject's own pre-trial metformin and/or sulphonylurea (SU) treatment | 110 |
| Total | 217 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Lack of Efficacy | 0 | 5 |
| Overall Study | Protocol Violation | 5 | 3 |
| Overall Study | Unclassified | 5 | 3 |
| Overall Study | Withdrawal Criteria | 2 | 4 |
Baseline characteristics
| Characteristic | Sita | Total | Comb |
|---|---|---|---|
| Age, Continuous | 57.10 years STANDARD_DEVIATION 8.41 | 56.90 years STANDARD_DEVIATION 9.19 | 56.70 years STANDARD_DEVIATION 9.96 |
| BMI | 31.90 kg/m^2 STANDARD_DEVIATION 5.91 | 31.85 kg/m^2 STANDARD_DEVIATION 5.56 | 31.79 kg/m^2 STANDARD_DEVIATION 5.2 |
| Body Weight | 88.2 kg STANDARD_DEVIATION 19.2 | 90.6 kg STANDARD_DEVIATION 19.8 | 93.1 kg STANDARD_DEVIATION 20.2 |
| Diabetes History | 9.90 years STANDARD_DEVIATION 5.65 | 9.74 years STANDARD_DEVIATION 5.63 | 9.58 years STANDARD_DEVIATION 5.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 101 Participants | 197 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 14 Participants | 8 Participants |
| FPG | 9.79 mmol/L STANDARD_DEVIATION 2.36 | 9.74 mmol/L STANDARD_DEVIATION 2.29 | 9.69 mmol/L STANDARD_DEVIATION 2.23 |
| HbA1c | 8.52 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.65 | 8.52 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.65 | 8.52 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.65 |
| Height | 1.66 meters STANDARD_DEVIATION 0.09 | 1.68 meters STANDARD_DEVIATION 0.1 | 1.71 meters STANDARD_DEVIATION 0.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 17 Participants | 30 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 3 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 | 7 Participants | 15 Participants | 8 Participants |
| Race (NIH/OMB) White | 84 Participants | 167 Participants | 83 Participants |
| Sex: Female, Male Female | 60 Participants | 99 Participants | 39 Participants |
| Sex: Female, Male Male | 50 Participants | 118 Participants | 68 Participants |
| Stratification Previous Metformin Monotherapy | 24 participants | 48 participants | 24 participants |
| Stratification Previous Metformin + Other OAD therapy | 86 participants | 169 participants | 83 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 76 / 107 | 72 / 110 |
| serious Total, serious adverse events | 2 / 107 | 4 / 110 |
Outcome results
Primary
HbA1c (Glycosylated Haemoglobin A1c)
Time frame: Week 26
Population: Sample size calculation: Assuming a standard deviation of 1.0 for HbA1c, 100 subjects in each treatment arm would be required to obtain a power of 80% for detecting a HbA1c difference of 0.4%. FAS (Full Analysis Set) is all randomised subjects exposed to at least one dose of trial product with a post baseline observation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Comb | HbA1c (Glycosylated Haemoglobin A1c) | 7.08 Percent (%) glycosylated haemoglobin | Standard Error 0.09 |
| Sita | HbA1c (Glycosylated Haemoglobin A1c) | 7.64 Percent (%) glycosylated haemoglobin | Standard Error 0.09 |
Comparison: Null hypothesis: Difference between mean HbA1c in the two treatment arms is equal to zero. Power calculation: Assuming a standard deviation of 1.0 for HbA1c, 100 subjects in each treatment arm would be required to obtain a power of 80% for detecting a HbA1c difference of 0.4%p-value: 0.00195% CI: [-0.77, -0.33]ANCOVA
Secondary
Change in BMI (Body Mass Index)
Time frame: Week 0, Week 26
Population: FAS (Full Analysis Set) is all randomised subjects exposed to at least one dose of trial product with a post baseline observation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Comb | Change in BMI (Body Mass Index) | -0.30 kg/m^2 | Standard Error 0.15 |
| Sita | Change in BMI (Body Mass Index) | -0.58 kg/m^2 | Standard Error 0.14 |
p-value: 0.12195% CI: [-0.07, 0.63]ANCOVA
Secondary
Change in Body Weight
Time frame: Week 0, Week 26
Population: FAS (Full Analysis Set) is all randomised subjects exposed to at least one dose of trial product with a post baseline observation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Comb | Change in Body Weight | -0.81 kg | Standard Error 0.44 |
| Sita | Change in Body Weight | -1.66 kg | Standard Error 0.42 |
p-value: 0.10995% CI: [-0.19, 1.88]ANCOVA
Secondary
FPG (Fasting Plasma Glucose)
Time frame: Week 26
Population: FAS (Full Analysis Set) is all randomised subjects exposed to at least one dose of trial product with a post baseline observation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Comb | FPG (Fasting Plasma Glucose) | 6.08 mmol/L | Standard Error 0.24 |
| Sita | FPG (Fasting Plasma Glucose) | 8.52 mmol/L | Standard Error 0.23 |
p-value: 0.00195% CI: [-3.01, -1.88]ANCOVA
Secondary
Hypoglycemic Episodes
Overall: All episodes. Minor: Symptomatic, with PG \< 3.1 mmol/L. Symptoms only: Symptomatic with PG ≥ 3.1 mmol/L
Time frame: Weeks 0-26
Population: SAS (safety analysis set) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Comb | Hypoglycemic Episodes | Overall | 1 episodes |
| Comb | Hypoglycemic Episodes | Minor | 0 episodes |
| Comb | Hypoglycemic Episodes | Symptoms Only | 0 episodes |
| Comb | Hypoglycemic Episodes | Unclassified | 0 episodes |
| Sita | Hypoglycemic Episodes | Unclassified | 0 episodes |
| Sita | Hypoglycemic Episodes | Overall | 1 episodes |
| Sita | Hypoglycemic Episodes | Symptoms Only | 0 episodes |
| Sita | Hypoglycemic Episodes | Minor | 0 episodes |
Secondary
Hypoglycemic Episodes: Day Time
Day time: Episodes between 6 pm and 11 am. Overall: All episodes. Minor: Symptomatic, with PG \< 3.1 mmol/L. Symptoms only: Symptomatic with PG ≥ 3.1 mmol/L
Time frame: Weeks 0-26
Population: SAS (safety analysis set) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Comb | Hypoglycemic Episodes: Day Time | Overall | 1 episodes |
| Comb | Hypoglycemic Episodes: Day Time | Minor | 0 episodes |
| Comb | Hypoglycemic Episodes: Day Time | Unclassified | 0 episodes |
| Comb | Hypoglycemic Episodes: Day Time | Symptoms Only | 0 episodes |
| Sita | Hypoglycemic Episodes: Day Time | Unclassified | 0 episodes |
| Sita | Hypoglycemic Episodes: Day Time | Minor | 0 episodes |
| Sita | Hypoglycemic Episodes: Day Time | Overall | 1 episodes |
| Sita | Hypoglycemic Episodes: Day Time | Symptoms Only | 0 episodes |
Secondary
Hypoglycemic Episodes: Night Time
Night time: Episodes between 11 am and 6 pm. Overall: All episodes. Minor: Symptomatic, with PG \< 3.1 mmol/L. Symptoms only: Symptomatic with PG ≥ 3.1 mmol/L
Time frame: Weeks 0-26
Population: SAS (safety analysis set) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Comb | Hypoglycemic Episodes: Night Time | Overall | 0 episodes |
| Comb | Hypoglycemic Episodes: Night Time | Minor | 0 episodes |
| Comb | Hypoglycemic Episodes: Night Time | Symptoms Only | 0 episodes |
| Comb | Hypoglycemic Episodes: Night Time | Unclassified | 0 episodes |
| Sita | Hypoglycemic Episodes: Night Time | Unclassified | 0 episodes |
| Sita | Hypoglycemic Episodes: Night Time | Overall | 0 episodes |
| Sita | Hypoglycemic Episodes: Night Time | Symptoms Only | 0 episodes |
| Sita | Hypoglycemic Episodes: Night Time | Minor | 0 episodes |
Secondary
Number of Subjects Achieving HbA1c Less Than or Equal to 6.5%
Time frame: Week 26
Population: FAS (Full Analysis Set) is all randomised subjects exposed to at least one dose of trial product with a post baseline observation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Comb | Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% | Target achieved | 20 Subjects |
| Comb | Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% | Target not achieved | 83 Subjects |
| Sita | Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% | Target achieved | 11 Subjects |
| Sita | Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% | Target not achieved | 95 Subjects |
Comparison: Null hypothesis: Odds ratio is equal to one.p-value: 0.06395% CI: [0.96, 5.2]Regression, Logistic
Secondary
Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% Without Symptomatic Hypoglycaemia
Symptomatic hypoglycaemia is biochemically confirmed hypoglycaemia or major hypoglycaemia
Time frame: Week 26
Population: FAS (Full Analysis Set) is all randomised subjects exposed to at least one dose of trial product with a post baseline observation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Comb | Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% Without Symptomatic Hypoglycaemia | Target achieved | 15 Subjects |
| Comb | Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% Without Symptomatic Hypoglycaemia | Target not achieved | 88 Subjects |
| Sita | Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% Without Symptomatic Hypoglycaemia | Target achieved | 8 Subjects |
| Sita | Number of Subjects Achieving HbA1c Less Than or Equal to 6.5% Without Symptomatic Hypoglycaemia | Target not achieved | 98 Subjects |
Comparison: Null hypothesis: Odds ratio is equal to one.p-value: 0.13595% CI: [0.8, 5.37]Regression, Logistic
Secondary
Number of Subjects Achieving HbA1c Less Than or Equal to 7.0%
Time frame: Week 26
Population: FAS (Full Analysis Set) is all randomised subjects exposed to at least one dose of trial product with a post baseline observation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Comb | Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% | Target achieved | 46 Subjects |
| Comb | Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% | Target not achieved | 57 Subjects |
| Sita | Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% | Target achieved | 25 Subjects |
| Sita | Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% | Target not achieved | 81 Subjects |
Comparison: Null hypothesis: Odds ratio is equal to one.p-value: 0.00195% CI: [1.65, 6.19]Regression, Logistic
Secondary
Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% Without Symptomatic Hypoglycaemia
Symptomatic hypoglycaemia is biochemically confirmed hypoglycaemia or major hypoglycaemia
Time frame: Week 26
Population: FAS (Full Analysis Set) is all randomised subjects exposed to at least one dose of trial product with a post baseline observation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Comb | Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% Without Symptomatic Hypoglycaemia | Target achieved | 37 Subjects |
| Comb | Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% Without Symptomatic Hypoglycaemia | Target not achieved | 66 Subjects |
| Sita | Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% Without Symptomatic Hypoglycaemia | Target achieved | 21 Subjects |
| Sita | Number of Subjects Achieving HbA1c Less Than or Equal to 7.0% Without Symptomatic Hypoglycaemia | Target not achieved | 85 Subjects |
Comparison: Null hypothesis: Odds ratio is equal to one.p-value: 0.00895% CI: [1.26, 4.81]Regression, Logistic
Secondary
Self-measured 9-point Plasma Glucose Profile
Time frame: Week 26
Population: FAS (Full Analysis Set) is all randomised subjects exposed to at least one dose of trial product with a post baseline observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Comb | Self-measured 9-point Plasma Glucose Profile | 120 minutes after start of breakfast | 8.82 mmol/L | Standard Error 0.28 |
| Comb | Self-measured 9-point Plasma Glucose Profile | 120 minutes after start of dinner | 9.30 mmol/L | Standard Error 0.32 |
| Comb | Self-measured 9-point Plasma Glucose Profile | 120 minutes after start of lunch | 8.69 mmol/L | Standard Error 0.28 |
| Comb | Self-measured 9-point Plasma Glucose Profile | Bedtime | 8.38 mmol/L | Standard Error 0.32 |
| Comb | Self-measured 9-point Plasma Glucose Profile | Before Lunch | 6.99 mmol/L | Standard Error 0.26 |
| Comb | Self-measured 9-point Plasma Glucose Profile | At 03:00 A.M. | 6.85 mmol/L | Standard Error 0.26 |
| Comb | Self-measured 9-point Plasma Glucose Profile | Before dinner | 7.85 mmol/L | Standard Error 0.31 |
| Comb | Self-measured 9-point Plasma Glucose Profile | Before breakfast the following day | 6.07 mmol/L | Standard Error 0.19 |
| Comb | Self-measured 9-point Plasma Glucose Profile | Before breakfast | 6.16 mmol/L | Standard Error 0.2 |
| Sita | Self-measured 9-point Plasma Glucose Profile | Before breakfast the following day | 7.87 mmol/L | Standard Error 0.19 |
| Sita | Self-measured 9-point Plasma Glucose Profile | Before breakfast | 8.17 mmol/L | Standard Error 0.2 |
| Sita | Self-measured 9-point Plasma Glucose Profile | 120 minutes after start of breakfast | 10.50 mmol/L | Standard Error 0.28 |
| Sita | Self-measured 9-point Plasma Glucose Profile | Before Lunch | 8.01 mmol/L | Standard Error 0.26 |
| Sita | Self-measured 9-point Plasma Glucose Profile | 120 minutes after start of lunch | 9.99 mmol/L | Standard Error 0.28 |
| Sita | Self-measured 9-point Plasma Glucose Profile | Before dinner | 8.61 mmol/L | Standard Error 0.31 |
| Sita | Self-measured 9-point Plasma Glucose Profile | 120 minutes after start of dinner | 10.20 mmol/L | Standard Error 0.32 |
| Sita | Self-measured 9-point Plasma Glucose Profile | Bedtime | 9.42 mmol/L | Standard Error 0.31 |
| Sita | Self-measured 9-point Plasma Glucose Profile | At 03:00 A.M. | 8.02 mmol/L | Standard Error 0.26 |
95% CI: [-2.5, -1.51]Linear Mixed-model
95% CI: [-2.4, -0.89]Linear Mixed-model
95% CI: [-1.69, -0.35]Linear Mixed-model
95% CI: [-2.05, -0.56]Linear mixed-model
95% CI: [-1.58, 0.05]Linear Mixed-model
95% CI: [-1.75, -0.02]Linear Mixed-model
95% CI: [-1.88, -0.2]Linear Mixed-model
95% CI: [-1.84, -0.49]Linear Mixed Model
95% CI: [-2.26, -1.34]Linear Mixed-model