Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The aim of this trial is to compare BIAsp 30 twice daily individually adjusted by the subject versus BIAsp 30 twice daily individually adjusted by the investigator both combined with oral antidiabetic drugs (OADs) in subjects with type 2 diabetes inadequately controlled with premixed human insulin. Subjects to continue their OAD background treatment: Metformin plus/minus alpha-glucosidase inhibitor.
Interventions
DRUGbiphasic insulin aspart 30
Dose individually adjusted, administered subcutaneously (s.c., under the skin) twice 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 65 Years
Healthy volunteers
No
Inclusion criteria
* Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial * Type 2 diabetes mellitus (diagnosed clinically) for at least 12 months * Currently treated with premixed/self-mixed human insulin (proportion of short-acting insulin is equal to or lower than 30%) BID (twice daily) combined with metformin with or without alpha-glucosidase inhibitor for at least 3 months prior to screening visit (Visit 1) with the minimum dose stated: Metformin: at least 1500 mg/day or maximum tolerated dose at least 1000 mg/day (with unchanged dosing within 3 months prior to Visit 1) OR alpha-glucosidase inhibitors: acarbose or miglitol at least 150 mg/day, or voglibose at least 0.6 mg/day * Total daily insulin dose below 1.4 IU/Kg * HbA1c above or equal to 7.0% and below or equal to 9.5% (central laboratory) * Body Mass Index (BMI) below or equal to 35.0 kg/m\^2
Exclusion criteria
* Treatment with any insulin secretagogue, thiazolidinedione (TZD), dipeptidyl peptidase-4 (DPP-4) inhibitors and Glucagon-like peptide-1 (GLP-1) receptor agonists within the last 3 months prior to Visit 1 * Previous use of insulin intensification treatment (premixed insulin thrice daily, basal bolus regimen, and continuous subcutaneous insulin infusion (CSII)) for more than 14 days * Previous use of any insulin other than premixed/self-mixed human insulin (proportion of short acting insulin equal to or lower than 30%) BID within 3 month prior to Visit 1 * Recurrent severe hypoglycaemia (more than 1 severe hypoglycaemic episode, during the last 12 months) or hypoglycaemic unawareness as judged by the investigator or hospitalisation for diabetic ketoacidosis during the previous 6 months * Known proliferative retinopathy or maculopathy requiring treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0, week 20 | Estimated mean change from baseline in HbA1c after 20 Weeks of treatment in full analysis set (FAS). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving HbA1c Below 7.0% | After 20 weeks of treatment | — |
| Percentage of Subjects Achieving HbA1c Below or Equal to 6.5% | After 20 weeks of treatment | — |
| Change From Baseline in FPG (Fasting Plasma Glucose) | Week 0, week 20 | — |
| Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only) | Week 0 to week 20 (inclusive). | Definition of a treatment emergent hypoglycemic episode: an episode occurred after the first administration of insulin or oral anti-diabetic drug, and no later than the last day on trial product. Severe hypoglycemic episode was that requiring assistance to administer carbohydrate, glucagon, or other resusciative actions. Minor hypoglycemic episode was the one with plasma glucose value \< 3.1 mmol/L, either with symptoms that could be handled by subject, or without symptoms. |
Countries
China
Participant flow
Recruitment details
Subjects were recruited from 23 sites in 1 country.
Pre-assignment details
Eligible subjects were randomised in a 1:1 manner to one of the 2 treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Subject-driven Titration Subjects were transferred on a 1:1 basis from pre-trial premixed/self-mixed human insulin to biphasic insulin aspart 30 (BIAsp 30). Individually adjusted BIAsp 30 was given immediately before breakfast and dinner during 20 weeks. Subjects were trained on how to adjust BIAsp 30 doses during the training period \[4 weeks\] and then were asked to adjust their BIAsp 30 doses by themselves during the maintenance period \[16 weeks\]. Subjects continued their pre-trial oral anti-diabetic drugs (OADs) (metformin and/or alpha-glucosidase inhibitor). OADs were kept unchanged in regimen and daily dose during this trial, and were administered orally according to local labels. | 172 |
| Investigator-driven Titration Subjects were transferred on a 1:1 basis from pre-trial premixed/self-mixed human insulin to biphasic insulin aspart 30 (BIAsp 30). Individually adjusted BIAsp 30 was given immediately before breakfast and dinner during 20 weeks. Subjects were asked to adjust their BIAsp 30 doses according to the directions from investigators throughout the trial period \[20 weeks\]. Subjects continued their pre-trial oral anti-diabetic drugs (OADs) (metformin and/or alpha-glucosidase inhibitor). OADs were kept unchanged in regimen and daily dose during this trial, and were administered orally according to local labels. | 172 |
| Total | 344 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Lack of Efficacy | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 4 |
| Overall Study | Unclassified | 4 | 5 |
| Overall Study | Withdrawal Criteria | 1 | 2 |
Baseline characteristics
| Characteristic | Subject-driven Titration | Investigator-driven Titration | Total |
|---|---|---|---|
| Age, Continuous | 54.8 years STANDARD_DEVIATION 7.3 | 53.4 years STANDARD_DEVIATION 7.5 | 54.1 years STANDARD_DEVIATION 7.4 |
| Body mass index (BMI) | 25.76 kg/m^2 STANDARD_DEVIATION 3.26 | 25.47 kg/m^2 STANDARD_DEVIATION 3.01 | 25.62 kg/m^2 STANDARD_DEVIATION 3.14 |
| Fasting Plasma Glucose | 8.83 mmol/L STANDARD_DEVIATION 2.36 | 9.07 mmol/L STANDARD_DEVIATION 2.43 | 8.95 mmol/L STANDARD_DEVIATION 2.4 |
| Gender Female | 79 Participants | 101 Participants | 180 Participants |
| Gender Male | 93 Participants | 71 Participants | 164 Participants |
| Glycosylated Haemoglobin (HbA1c) | 8.10 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.64 | 8.14 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.67 | 8.12 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.65 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 172 Participants | 172 Participants | 344 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 |
| Weight | 70.3 kg STANDARD_DEVIATION 11.3 | 69.5 kg STANDARD_DEVIATION 11.6 | 69.9 kg STANDARD_DEVIATION 11.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 172 | 13 / 172 |
| serious Total, serious adverse events | 4 / 172 | 7 / 172 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Estimated mean change from baseline in HbA1c after 20 Weeks of treatment in full analysis set (FAS).
Time frame: Week 0, week 20
Population: Full analysis set (FAS) - included all randomised subjects and missing data was imputed using last observation carried forward (LOCF) where any post-randomisation measurements were available. Six subjects did not contribute to FAS due to lack of post-randomisation measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subject-driven Titration | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -1.32 percentage of glycosylated haemoglobin | Standard Deviation 0.86 |
| Investigator-driven Titration | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -1.31 percentage of glycosylated haemoglobin | Standard Deviation 0.96 |
Comparison: FAS95% CI: [-0.19, 0.14]Regression, Linear
Secondary
Change From Baseline in FPG (Fasting Plasma Glucose)
Time frame: Week 0, week 20
Population: Full analysis set (FAS) - included all randomized subjects and missing data was imputed using last observation carried forward (LOCF) where any post-randomization measurements were available. Seven subjects did not contribute to FAS due to lack of post-randomization measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subject-driven Titration | Change From Baseline in FPG (Fasting Plasma Glucose) | -1.26 mmol/L | Standard Deviation 2.59 |
| Investigator-driven Titration | Change From Baseline in FPG (Fasting Plasma Glucose) | -1.48 mmol/L | Standard Deviation 3.01 |
Secondary
Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only)
Definition of a treatment emergent hypoglycemic episode: an episode occurred after the first administration of insulin or oral anti-diabetic drug, and no later than the last day on trial product. Severe hypoglycemic episode was that requiring assistance to administer carbohydrate, glucagon, or other resusciative actions. Minor hypoglycemic episode was the one with plasma glucose value \< 3.1 mmol/L, either with symptoms that could be handled by subject, or without symptoms.
Time frame: Week 0 to week 20 (inclusive).
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of biphasic insulin aspart 30.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subject-driven Titration | Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only) | All hypoglycemic events | 10.04 events per patient per year |
| Subject-driven Titration | Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only) | Severe hypoglycemic events | 0.02 events per patient per year |
| Subject-driven Titration | Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only) | Minor hypoglycemic events | 1.70 events per patient per year |
| Subject-driven Titration | Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only) | Probable symptomatic hypoglycemia | 0.45 events per patient per year |
| Investigator-driven Titration | Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only) | Probable symptomatic hypoglycemia | 0.56 events per patient per year |
| Investigator-driven Titration | Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only) | All hypoglycemic events | 10.90 events per patient per year |
| Investigator-driven Titration | Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only) | Minor hypoglycemic events | 1.66 events per patient per year |
| Investigator-driven Titration | Incidence of Hypoglycaemic Episodes (All, Major, Minor and Symptoms Only) | Severe hypoglycemic events | 0.02 events per patient per year |
Secondary
Percentage of Subjects Achieving HbA1c Below 7.0%
Time frame: After 20 weeks of treatment
Population: Full analysis set (FAS) - included all randomized subjects and missing data was imputed using last observation carried forward (LOCF) where any post-randomization measurements were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Subject-driven Titration | Percentage of Subjects Achieving HbA1c Below 7.0% | 64.5 percentage (%) of subjects |
| Investigator-driven Titration | Percentage of Subjects Achieving HbA1c Below 7.0% | 58.1 percentage (%) of subjects |
Secondary
Percentage of Subjects Achieving HbA1c Below or Equal to 6.5%
Time frame: After 20 weeks of treatment
Population: Full analysis set (FAS) - included all randomized subjects and missing data was imputed using last observation carried forward (LOCF) where any post-randomization measurements were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Subject-driven Titration | Percentage of Subjects Achieving HbA1c Below or Equal to 6.5% | 35.5 percentage (%) of subjects |
| Investigator-driven Titration | Percentage of Subjects Achieving HbA1c Below or Equal to 6.5% | 37.2 percentage (%) of subjects |