Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The aim of this trial is to compare efficacy and safety of insulin detemir plus insulin aspart and NPH insulin plus human soluble insulin both in a basal bolus regimen with or without metformin in Chinese patients with type 2 diabetes. The trial adopts a group sequential design, where the analysis of the primary efficacy endpoint will be performed at the interim analysis, in addition to the final formal analysis. The decision to continue or stop the trial will be based on the result of the interim analysis.
Interventions
DRUGinsulin detemir
Dose individually adjusted. Administered subcutaneously/s.c. (under the skin) once daily using NovoPen®4
DRUGinsulin aspart
Dose individually adjusted. Administered subcutaneously/s.c. (under the skin) three times a day before a meal using NovoPen®4
DRUGinsulin NPH
Dose individually adjusted. Administered subcutaneously/s.c. (under the skin) once daily using NovoPen®4
Dose individually adjusted. Administered subcutaneously/s.c. (under the skin) three times a day before a meal using NovoPen®4
DRUGmetformin
For subjects previously treated with metformin, the dosage and frequency will be kept unchanged
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 (diagnosed clinically) for at 12 months or longer * Currently treated with basal insulin once daily or premixed insulin twice daily for at least 3 months with or without OAD(s), and total daily insulin dose less than 1.4 IU (U)/kg (If treated with metformin, unchanged total daily dose of at least 1000 mg for at least 3 months) * Body Mass Index (BMI) equal to 40 kg/m\^2 or below * HbA1c (glycosylated haemoglobin A1c) between 7.0% and 10.0% by central laboratory analysis * Plan to be admitted for optimising glycaemic control at least 2 days prior to the randomisation
Exclusion criteria
* Treatment with thiazolidinediones (TZD) or Glucagon-Like Peptide-1 (GLP-1) receptor agonists within the last 3 months prior to the screening * Anticipated change after the randomisation in concomitant medication known to interfere with glucose metabolism, such as systemic corticosteroids, beta-blockers and mono amine oxidase (MAO) inhibitors * Previous participation in this trial (participation is defined as randomised. Re-screening of screening failures is allowed only once within the limits of the recruitment period.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean 8-point Plasma Glucose (PG) After Two Weeks of Treatment | Week 0, week 2 | Mean value of 8-point PG was the arithmetic mean of all 8 time-instant PG values of the 8-point PG profile. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean 2-hour Post Prandial Plasma Glucose (2hPPG) of 3 Meals After Two Weeks of Treatment | Week 0, week 2 | The mean 2hPPG was derived from the 8-point PG profile as the mean value of the available 120 minutes after each meal. |
| Change From Baseline in Mean Value of Pre-lunch, Pre-dinner and Bedtime PG After Two Weeks of Treatment | Week 0, week 2 | The mean value of pre-lunch, pre-dinner and bedtime PG was derived from the 8-point PG profile measured before lunch, dinner and bedtime. |
| Percentage of Subjects Achieving FPG < 6.0 mmol / L After Two Weeks of Treatment | Week 2 | — |
| Percentage of Subjects Achieving Mean 2hPPG of 3 Meals < 8.0 mmol / L After Two Weeks of Treatment | Week 2 | — |
| Change From Baseline in Fasting Plasma Glucose (FPG) After Two Weeks of Treatment | Week 0, week 2 | The FPG referred to pre-breakfast plasma glucose. |
| Percentage of Subjects Achieving FPG Target Without Nocturnal Hypoglycaemia After Two Weeks of Treatment | Week 2 | FPG target was \< 6.0 mmol / L. Nocturnal hypoglycaemia was defined as a hypoglycaemic episode happened between 00:01 and 05:59 a.m. (both included). |
| Change From Baseline in Fructosamine After Two Weeks of Treatment | Week 0, week 2 | — |
| Incidence of Hypoglycaemic Episodes | Weeks 0-2 | All events summarized were treatment emergent hypoglycaemic events. Hypoglycaemic episodes were summarized based on the ADA classification and also according to an additional definition. Severe hypoglycemia: ADA definition. Minor hypoglycaemic episode: an episode with symptoms with confirmation by plasma glucose (PG) \< 3.1 mmol/l (56 mg/dl) and was handled by the subject himself/herself, or any asymptomatic PG value \< 3.1 mmol/l (56 mg/dl). A hypoglycaemia episode was defined as nocturnal if the time of onset was between 00:01 and 05:59 a.m. (both included), otherwise it was diurnal. |
| Percentage of Subjects Achieving Both FPG and 2hPPG Targets After Two Weeks of Treatment | Week 2 | FPG target was \< 6.0 mmol / L, 2hPPG target was \< 8.0 mmol / L. |
Countries
China
Participant flow
Recruitment details
A total of 6 centres in China participated.
Pre-assignment details
Between screening and treatment with trial drugs, subjects were assessed for eligibility and were randomised 1:1 into one of the two treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin Insulin detemir was administered subcutaneously in the thigh once daily at bedtime as basal insulin. Insulin aspart was injected in the abdominal area subcutaneously 0\
5 minutes before each meal as bolus insulin. Metformin was given to subjects who were taking metformin before this trial. | 29 |
| Insulin NPH + Human Soluble Insulin ± Metformin Insulin NPH was administered subcutaneously in the thigh once daily at bedtime as basal insulin. Human Soluble insulin was injected in the abdominal area subcutaneously 30 minutes before each meal as bolus insulin. Metformin was given to subjects who were taking metformin before this trial. | 29 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Insulin Detemir + Insulin Aspart ± Metformin | Insulin NPH + Human Soluble Insulin ± Metformin | Total |
|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 10.2 | 55.8 years STANDARD_DEVIATION 9.8 | 56.7 years STANDARD_DEVIATION 9.9 |
| Body mass index (BMI) | 26.09 kg/m^2 STANDARD_DEVIATION 3.13 | 24.63 kg/m^2 STANDARD_DEVIATION 2.67 | 25.36 kg/m^2 STANDARD_DEVIATION 2.98 |
| Diabetes complications Diabetic complications | 13 participants | 15 participants | 28 participants |
| Diabetes complications Diabetic Nephropathy | 4 participants | 3 participants | 7 participants |
| Diabetes complications Diabetic neuropathy | 10 participants | 11 participants | 21 participants |
| Diabetes complications Diabetic retinopathy | 7 participants | 8 participants | 15 participants |
| Diabetes complications Macroangiopathy | 2 participants | 5 participants | 7 participants |
| Duration of diagnosed diabetes | 10.23 years STANDARD_DEVIATION 5.08 | 11.97 years STANDARD_DEVIATION 7.14 | 11.10 years STANDARD_DEVIATION 6.2 |
| Glycosylated haemoglobin A1c (HbA1c) | 8.76 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.73 | 8.49 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.76 | 8.62 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.75 |
| Height | 164.2 cm STANDARD_DEVIATION 8.5 | 164.2 cm STANDARD_DEVIATION 8.4 | 164.2 cm STANDARD_DEVIATION 8.4 |
| Pre-trial insulin treatment basal insulin (once daily) | 6 participants | 7 participants | 13 participants |
| Pre-trial insulin treatment premixed insulin (twice daily) | 23 participants | 22 participants | 45 participants |
| Pre-trial treatment of oral antidiabetic drug Acarbose | 9 participants | 10 participants | 19 participants |
| Pre-trial treatment of oral antidiabetic drug Gliclazide | 0 participants | 3 participants | 3 participants |
| Pre-trial treatment of oral antidiabetic drug Glimepiride | 2 participants | 4 participants | 6 participants |
| Pre-trial treatment of oral antidiabetic drug Metformin | 13 participants | 8 participants | 21 participants |
| Pre-trial treatment of oral antidiabetic drug Metformin hydrochloride | 2 participants | 3 participants | 5 participants |
| Pre-trial treatment of oral antidiabetic drug Repaglinide | 2 participants | 2 participants | 4 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 29 Participants | 29 Participants | 58 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 14 Participants | 15 Participants | 29 Participants |
| Sex: Female, Male Male | 15 Participants | 14 Participants | 29 Participants |
| Type 2 diabetes | 29 participants | 29 participants | 58 participants |
| Weight | 70.9 kg STANDARD_DEVIATION 13.1 | 66.5 kg STANDARD_DEVIATION 9 | 68.7 kg STANDARD_DEVIATION 11.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 29 | 2 / 29 |
| serious Total, serious adverse events | 0 / 29 | 0 / 29 |
Outcome results
Primary
Change From Baseline in Mean 8-point Plasma Glucose (PG) After Two Weeks of Treatment
Mean value of 8-point PG was the arithmetic mean of all 8 time-instant PG values of the 8-point PG profile.
Time frame: Week 0, week 2
Population: Full analysis set using LOCF (Last Observation Carried Forward) included all randomised subject. The 2 subjects who withdrew after randomisation were excluded from the efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Change From Baseline in Mean 8-point Plasma Glucose (PG) After Two Weeks of Treatment | -2.84 mmol/L | Standard Error 0.27 |
| Insulin NPH + Human Soluble Insulin ± Metformin | Change From Baseline in Mean 8-point Plasma Glucose (PG) After Two Weeks of Treatment | -2.80 mmol/L | Standard Error 0.28 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) After Two Weeks of Treatment
The FPG referred to pre-breakfast plasma glucose.
Time frame: Week 0, week 2
Population: Full analysis set using LOCF (Last Observation Carried Forward) included all randomised subject. The 2 subjects who withdrew after randomisation were excluded from the efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Change From Baseline in Fasting Plasma Glucose (FPG) After Two Weeks of Treatment | -2.22 mmol/L | Standard Error 0.34 |
| Insulin NPH + Human Soluble Insulin ± Metformin | Change From Baseline in Fasting Plasma Glucose (FPG) After Two Weeks of Treatment | -2.29 mmol/L | Standard Error 0.35 |
Secondary
Change From Baseline in Fructosamine After Two Weeks of Treatment
Time frame: Week 0, week 2
Population: Full analysis set using LOCF (Last Observation Carried Forward) included all randomised subject. The 2 subjects who withdrew after randomisation were excluded from the efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Change From Baseline in Fructosamine After Two Weeks of Treatment | -31.0 Umol/L | Standard Error 5.37 |
| Insulin NPH + Human Soluble Insulin ± Metformin | Change From Baseline in Fructosamine After Two Weeks of Treatment | -23.7 Umol/L | Standard Error 5.5 |
Secondary
Change From Baseline in Mean 2-hour Post Prandial Plasma Glucose (2hPPG) of 3 Meals After Two Weeks of Treatment
The mean 2hPPG was derived from the 8-point PG profile as the mean value of the available 120 minutes after each meal.
Time frame: Week 0, week 2
Population: Full analysis set using LOCF (Last Observation Carried Forward) included all randomised subject. The 2 subjects who withdrew after randomisation were excluded from the efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Change From Baseline in Mean 2-hour Post Prandial Plasma Glucose (2hPPG) of 3 Meals After Two Weeks of Treatment | -4.00 mmol/L | Standard Error 0.39 |
| Insulin NPH + Human Soluble Insulin ± Metformin | Change From Baseline in Mean 2-hour Post Prandial Plasma Glucose (2hPPG) of 3 Meals After Two Weeks of Treatment | -3.47 mmol/L | Standard Error 0.4 |
Secondary
Change From Baseline in Mean Value of Pre-lunch, Pre-dinner and Bedtime PG After Two Weeks of Treatment
The mean value of pre-lunch, pre-dinner and bedtime PG was derived from the 8-point PG profile measured before lunch, dinner and bedtime.
Time frame: Week 0, week 2
Population: Full analysis set using LOCF (Last Observation Carried Forward) included all randomised subject. The 2 subjects who withdrew after randomisation were excluded from the efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Change From Baseline in Mean Value of Pre-lunch, Pre-dinner and Bedtime PG After Two Weeks of Treatment | -2.47 mmol/L | Standard Error 0.38 |
| Insulin NPH + Human Soluble Insulin ± Metformin | Change From Baseline in Mean Value of Pre-lunch, Pre-dinner and Bedtime PG After Two Weeks of Treatment | -2.87 mmol/L | Standard Error 0.38 |
Secondary
Incidence of Hypoglycaemic Episodes
All events summarized were treatment emergent hypoglycaemic events. Hypoglycaemic episodes were summarized based on the ADA classification and also according to an additional definition. Severe hypoglycemia: ADA definition. Minor hypoglycaemic episode: an episode with symptoms with confirmation by plasma glucose (PG) \< 3.1 mmol/l (56 mg/dl) and was handled by the subject himself/herself, or any asymptomatic PG value \< 3.1 mmol/l (56 mg/dl). A hypoglycaemia episode was defined as nocturnal if the time of onset was between 00:01 and 05:59 a.m. (both included), otherwise it was diurnal.
Time frame: Weeks 0-2
Population: Safety analysis set included all subjects receiving at least one dose of the trial products.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Incidence of Hypoglycaemic Episodes | Diurnal | 18 events |
| Insulin Detemir + Insulin Aspart ± Metformin | Incidence of Hypoglycaemic Episodes | Nocturnal | 4 events |
| Insulin Detemir + Insulin Aspart ± Metformin | Incidence of Hypoglycaemic Episodes | Severe | 0 events |
| Insulin Detemir + Insulin Aspart ± Metformin | Incidence of Hypoglycaemic Episodes | Minor | 2 events |
| Insulin Detemir + Insulin Aspart ± Metformin | Incidence of Hypoglycaemic Episodes | All events | 22 events |
| Insulin NPH + Human Soluble Insulin ± Metformin | Incidence of Hypoglycaemic Episodes | Diurnal | 43 events |
| Insulin NPH + Human Soluble Insulin ± Metformin | Incidence of Hypoglycaemic Episodes | All events | 54 events |
| Insulin NPH + Human Soluble Insulin ± Metformin | Incidence of Hypoglycaemic Episodes | Minor | 11 events |
| Insulin NPH + Human Soluble Insulin ± Metformin | Incidence of Hypoglycaemic Episodes | Severe | 0 events |
| Insulin NPH + Human Soluble Insulin ± Metformin | Incidence of Hypoglycaemic Episodes | Nocturnal | 11 events |
Secondary
Percentage of Subjects Achieving Both FPG and 2hPPG Targets After Two Weeks of Treatment
FPG target was \< 6.0 mmol / L, 2hPPG target was \< 8.0 mmol / L.
Time frame: Week 2
Population: Full analysis set using LOCF (Last Observation Carried Forward) included all randomised subject.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Percentage of Subjects Achieving Both FPG and 2hPPG Targets After Two Weeks of Treatment | 20.7 percentage (%) of subjects |
| Insulin NPH + Human Soluble Insulin ± Metformin | Percentage of Subjects Achieving Both FPG and 2hPPG Targets After Two Weeks of Treatment | 20.7 percentage (%) of subjects |
Secondary
Percentage of Subjects Achieving FPG < 6.0 mmol / L After Two Weeks of Treatment
Time frame: Week 2
Population: Full analysis set using LOCF (Last Observation Carried Forward) included all randomised subject.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Percentage of Subjects Achieving FPG < 6.0 mmol / L After Two Weeks of Treatment | 48.3 percentage (%) of subjects |
| Insulin NPH + Human Soluble Insulin ± Metformin | Percentage of Subjects Achieving FPG < 6.0 mmol / L After Two Weeks of Treatment | 48.3 percentage (%) of subjects |
Secondary
Percentage of Subjects Achieving FPG Target Without Nocturnal Hypoglycaemia After Two Weeks of Treatment
FPG target was \< 6.0 mmol / L. Nocturnal hypoglycaemia was defined as a hypoglycaemic episode happened between 00:01 and 05:59 a.m. (both included).
Time frame: Week 2
Population: Full analysis set using LOCF (Last Observation Carried Forward) included all randomised subject.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Percentage of Subjects Achieving FPG Target Without Nocturnal Hypoglycaemia After Two Weeks of Treatment | 41.4 percentage (%) of subjects |
| Insulin NPH + Human Soluble Insulin ± Metformin | Percentage of Subjects Achieving FPG Target Without Nocturnal Hypoglycaemia After Two Weeks of Treatment | 34.5 percentage (%) of subjects |
Secondary
Percentage of Subjects Achieving Mean 2hPPG of 3 Meals < 8.0 mmol / L After Two Weeks of Treatment
Time frame: Week 2
Population: Full analysis set using LOCF (Last Observation Carried Forward) included all randomised subject.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Detemir + Insulin Aspart ± Metformin | Percentage of Subjects Achieving Mean 2hPPG of 3 Meals < 8.0 mmol / L After Two Weeks of Treatment | 41.4 percentage (%) of subjects |
| Insulin NPH + Human Soluble Insulin ± Metformin | Percentage of Subjects Achieving Mean 2hPPG of 3 Meals < 8.0 mmol / L After Two Weeks of Treatment | 34.5 percentage (%) of subjects |