Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe, and North and South America. The aim of this trial is to investigate if a dietary intervention has an effect on weight when initiating insulin treatment in subjects with type 2 diabetes currently treated with oral antidiabetic drugs (OADs).
Interventions
DRUGInsulin detemir
Individually adjusted insulin detemir subcutaneously (under the skin) once daily. Subjects continue their pre-trial metformin treatment.
DIETARY_SUPPLEMENTDietary regimen
Subjects receive dietary consultation by a dietician at six occasions during the trial.
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 (diagnosed clinically) for at least 6 months prior trial start * Insulin naive subjects * HbA1c: 7.0-9.0 % (both inclusive) * Body Mass Index (BMI): 25.0-45.0 kg/m\^2 (both inclusive)
Exclusion criteria
* Use of Thiazolidinedione (TZDs) or Glucagon-like peptide-1 analogue (GLP- 1) receptor agonists within the last 3 months prior to trial enrollment * Cardiovascular disease within the last 6 months * Recurrent severe hypoglycaemia or hypoglycaemic unawareness or hospitalisation for diabetic ketoacidosis during the previous 6 months * Uncontrolled treated/untreated severe hypertension, impaired liver function, impaired renal function, known proliferative retinopathy or maculopathy requiring treatment * Cancer and medical history of cancer in the past 5 years (except basal cell skin cancer or squamous cell skin cancer) * Pregnancy, breast-feeding, the intention of becoming pregnant or not using adequate contraceptive measures according to local requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight | Week 0, Week 26 | Estimated mean change from baseline in body weight after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Haemoglobin (HbA1c) | Week 0, Week 26 | Estimated mean change from baseline in HbA1c after 26 weeks of treatment. |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Week 0, Week 26 | Estimated mean change from baseline in FPG after 26 weeks of treatment. |
| Change From Baseline in Body Mass Index (BMI) | Week 0, Week 26 | Estimated mean change from baseline in BMI after 26 weeks of treatment. |
| Rate of All Treatment Emergent Hypoglycaemic Episodes | Week 0 to Week 26 | Corresponds to rate of treatment emergent hypoglycaemic episodes per patient exposure year. A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment. Severe, if assistance was required to actively administer carbohydrate, glucagons or other resuscitative actions. |
| Rate of Nocturnal Treatment Emergent Hypoglycaemic Episodes | Week 0 to Week 26 | Corresponds to rate of treatment emergent hypoglycaemic episodes per patient exposure year. A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment. A hypoglycaemic episode with time of onset between 00:01 and 05:59 a.m. (both included) was considered nocturnal. Severe, if assistance was required to actively administer carbohydrate, glucagons or other resuscitative actions. |
| Rate of Treatment Emergent Adverse Events (TEAEs) | Week 0 to Week 26 | Corresponds to rate of adverse events (AEs) per 100 patient years of exposure. Mild AEs: no or transient symptoms, no interference with subject's daily activities. Moderate AEs: marked symptoms, moderate interference with subject's daily activities. Severe AEs: considerable interference with subject's daily activities, unacceptable. Serious AEs: AEs that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalization, persistent/significant disability/incapacity/congenital anomaly/birth defect. |
Countries
Argentina, Germany, Poland, Puerto Rico, Russia, Serbia, Slovakia, Slovenia, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
The trial was conducted at 110 sites in 9 countries: Argentina (5), Germany (7), Poland (4), Serbia (4), Slovakia (3), Slovenia (2), Spain (4), Turkey (5) and United States of America (76).
Pre-assignment details
Subjects continued on their treatment with metformin, at the pre-randomisation dose level and dosing frequency. All other oral antidiabetic drugs were discontinued before insulin detemir was used.
Participants by arm
| Arm | Count |
|---|---|
| Dietician Insulin detemir (Levemir®) 100 U/mL, was injected subcutaneously once daily with the evening meal or at bedtime as add-on to subject's pre-trial treatment of metformin for 26 weeks. Subjects received dietary consultation according to local standard during 3 face-to-face meetings and 3 phone contacts. Insulin doses were individually adjusted. | 305 |
| Control Insulin detemir (Levemir®) 100 U/mL, was injected subcutaneously once daily with the evening meal or at bedtime as add-on to subject's pre-trial treatment of metformin for 26 weeks. Subjects did not receive dietary consultation except for basic dietary advice at baseline. Insulin doses were individually adjusted. | 301 |
| Total | 606 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 8 |
| Overall Study | Lack of Efficacy | 1 | 5 |
| Overall Study | Other | 21 | 18 |
| Overall Study | Protocol Violation | 13 | 11 |
| Overall Study | Withdrawal Criteria | 12 | 21 |
Baseline characteristics
| Characteristic | Dietician | Total | Control |
|---|---|---|---|
| Age, Continuous | 58.2 years STANDARD_DEVIATION 9.7 | 57.4 years STANDARD_DEVIATION 9.9 | 56.5 years STANDARD_DEVIATION 10 |
| Body mass index (BMI) | 34.4 kg/m^2 STANDARD_DEVIATION 5.4 | 34.4 kg/m^2 STANDARD_DEVIATION 5.5 | 34.3 kg/m^2 STANDARD_DEVIATION 5.6 |
| Body weight | 96.4 kg STANDARD_DEVIATION 18.2 | 96.7 kg STANDARD_DEVIATION 19.3 | 97.0 kg STANDARD_DEVIATION 20.4 |
| Duration of diabetes | 8.6 years STANDARD_DEVIATION 5.8 | 8.6 years STANDARD_DEVIATION 5.9 | 8.5 years STANDARD_DEVIATION 6 |
| Fasting plasma glucose (FPG) | 9.3 mmol/L STANDARD_DEVIATION 2.3 | 9.2 mmol/L STANDARD_DEVIATION 2.2 | 9.2 mmol/L STANDARD_DEVIATION 2 |
| Glycosylated haemoglobin (HbA1c) | 8.0 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.7 | 7.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 |
| Height | 1.67 meters STANDARD_DEVIATION 0.1 | 1.67 meters STANDARD_DEVIATION 0.1 | 1.68 meters STANDARD_DEVIATION 0.1 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 7 participants | 5 participants |
| Race/Ethnicity, Customized Black or African American | 21 participants | 47 participants | 26 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 63 participants | 141 participants | 78 participants |
| Race/Ethnicity, Customized Native Hawaiian or Oth. Pacific Islander | 3 participants | 3 participants | 0 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 242 participants | 465 participants | 223 participants |
| Race/Ethnicity, Customized Other | 5 participants | 7 participants | 2 participants |
| Race/Ethnicity, Customized White | 274 participants | 542 participants | 268 participants |
| Sex: Female, Male Female | 152 Participants | 295 Participants | 143 Participants |
| Sex: Female, Male Male | 153 Participants | 311 Participants | 158 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 61 / 305 | 69 / 301 |
| serious Total, serious adverse events | 17 / 305 | 19 / 301 |
Outcome results
Primary
Change From Baseline in Body Weight
Estimated mean change from baseline in body weight after 26 weeks of treatment.
Time frame: Week 0, Week 26
Population: Full analysis set (FAS) includes all randomised subjects and missing data is imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dietician | Change From Baseline in Body Weight | -1.05 kg | Standard Error 0.23 |
| Control | Change From Baseline in Body Weight | -0.56 kg | Standard Error 0.23 |
Comparison: Normal linear regression model with treatment, strata, use of insulin secretagogue at screening, sex and region as factors and age and weight at baseline as covariates. Superiority was considered confirmed if the upper bound of the two-sided 95% CI for the estimated treatment difference (dietary intervention versus no dietary intervention), which was calculated using the FAS, was below 0 kg.p-value: 0.13295% CI: [-0.15, 1.13]Regression, Linear
Secondary
Change From Baseline in Body Mass Index (BMI)
Estimated mean change from baseline in BMI after 26 weeks of treatment.
Time frame: Week 0, Week 26
Population: Full analysis set (FAS) includes all randomised subjects and missing data is imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dietician | Change From Baseline in Body Mass Index (BMI) | -0.37 kg/m^2 | Standard Error 0.08 |
| Control | Change From Baseline in Body Mass Index (BMI) | -0.20 kg/m^2 | Standard Error 0.08 |
Comparison: Normal linear regression model with treatment, use of insulin secretagogue at screening, sex and region as factors, and age and BMI at baseline as covariates.p-value: 0.13795% CI: [-0.05, 0.39]Regression, Linear
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Estimated mean change from baseline in FPG after 26 weeks of treatment.
Time frame: Week 0, Week 26
Population: Full analysis set (FAS) includes all randomised subjects and missing data is imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dietician | Change From Baseline in Fasting Plasma Glucose (FPG) | -3.00 mmol/L | Standard Error 0.12 |
| Control | Change From Baseline in Fasting Plasma Glucose (FPG) | -2.93 mmol/L | Standard Error 0.12 |
Comparison: Normal linear regression model with treatment, strata, use of insulin secretagogue at screening and region as factors and FPG at baseline as covariate.p-value: 0.67495% CI: [-0.25, 0.39]Regression, Linear
Secondary
Change From Baseline in Glycosylated Haemoglobin (HbA1c)
Estimated mean change from baseline in HbA1c after 26 weeks of treatment.
Time frame: Week 0, Week 26
Population: Full analysis set (FAS) includes all randomised subjects and missing data is imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dietician | Change From Baseline in Glycosylated Haemoglobin (HbA1c) | -0.93 percentage of glycosylated haemoglobin | Standard Error 0.05 |
| Control | Change From Baseline in Glycosylated Haemoglobin (HbA1c) | -0.80 percentage of glycosylated haemoglobin | Standard Error 0.05 |
Comparison: Normal linear regression model with treatment, strata, use of insulin secretagogue at screening and region as factors and HbA1c at baseline as covariate.p-value: 0.05395% CI: [0, 0.26]Regression, Linear
Secondary
Rate of All Treatment Emergent Hypoglycaemic Episodes
Corresponds to rate of treatment emergent hypoglycaemic episodes per patient exposure year. A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment. Severe, if assistance was required to actively administer carbohydrate, glucagons or other resuscitative actions.
Time frame: Week 0 to Week 26
Population: Safety analysis set includes all subjects who received at least one dose of insulin detemir.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dietician | Rate of All Treatment Emergent Hypoglycaemic Episodes | All Events | 25.47 rate per year of patient exposure |
| Dietician | Rate of All Treatment Emergent Hypoglycaemic Episodes | Severe Events | 0.01 rate per year of patient exposure |
| Control | Rate of All Treatment Emergent Hypoglycaemic Episodes | All Events | 23.30 rate per year of patient exposure |
| Control | Rate of All Treatment Emergent Hypoglycaemic Episodes | Severe Events | 0.01 rate per year of patient exposure |
Secondary
Rate of Nocturnal Treatment Emergent Hypoglycaemic Episodes
Corresponds to rate of treatment emergent hypoglycaemic episodes per patient exposure year. A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment. A hypoglycaemic episode with time of onset between 00:01 and 05:59 a.m. (both included) was considered nocturnal. Severe, if assistance was required to actively administer carbohydrate, glucagons or other resuscitative actions.
Time frame: Week 0 to Week 26
Population: Safety analysis set includes all subjects who received at least one dose of insulin detemir.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dietician | Rate of Nocturnal Treatment Emergent Hypoglycaemic Episodes | All Events | 5.59 rate per year of patient exposure |
| Dietician | Rate of Nocturnal Treatment Emergent Hypoglycaemic Episodes | Severe Events | 0.01 rate per year of patient exposure |
| Control | Rate of Nocturnal Treatment Emergent Hypoglycaemic Episodes | All Events | 5.51 rate per year of patient exposure |
| Control | Rate of Nocturnal Treatment Emergent Hypoglycaemic Episodes | Severe Events | 0.01 rate per year of patient exposure |
Secondary
Rate of Treatment Emergent Adverse Events (TEAEs)
Corresponds to rate of adverse events (AEs) per 100 patient years of exposure. Mild AEs: no or transient symptoms, no interference with subject's daily activities. Moderate AEs: marked symptoms, moderate interference with subject's daily activities. Severe AEs: considerable interference with subject's daily activities, unacceptable. Serious AEs: AEs that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalization, persistent/significant disability/incapacity/congenital anomaly/birth defect.
Time frame: Week 0 to Week 26
Population: Safety analysis set includes all subjects who received at least one dose of insulin detemir.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dietician | Rate of Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 16.3 rate per 100 years of patient exposure |
| Dietician | Rate of Treatment Emergent Adverse Events (TEAEs) | Moderate TEAEs | 130.5 rate per 100 years of patient exposure |
| Dietician | Rate of Treatment Emergent Adverse Events (TEAEs) | Severe TEAEs | 16.3 rate per 100 years of patient exposure |
| Dietician | Rate of Treatment Emergent Adverse Events (TEAEs) | Mild TEAEs | 241.0 rate per 100 years of patient exposure |
| Dietician | Rate of Treatment Emergent Adverse Events (TEAEs) | All TEAEs | 387.9 rate per 100 years of patient exposure |
| Control | Rate of Treatment Emergent Adverse Events (TEAEs) | Mild TEAEs | 317.5 rate per 100 years of patient exposure |
| Control | Rate of Treatment Emergent Adverse Events (TEAEs) | All TEAEs | 437.1 rate per 100 years of patient exposure |
| Control | Rate of Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 16.6 rate per 100 years of patient exposure |
| Control | Rate of Treatment Emergent Adverse Events (TEAEs) | Severe TEAEs | 11.3 rate per 100 years of patient exposure |
| Control | Rate of Treatment Emergent Adverse Events (TEAEs) | Moderate TEAEs | 108.3 rate per 100 years of patient exposure |