Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial was conducted in Asia, Europe and South America. The aim of this trial was to confirm efficacy of subject driven titration (individually adjusted) of biphasic insulin aspart 30 (BIAsp 30) twice daily in terms of glycaemic control assessed by change in glycosylated haemoglobin (HbA1c).
Interventions
DRUGbiphasic insulin aspart 30
Administered subcutaneously (under the skin) using FlexPen® twice daily for 20 weeks. Directions for use were given to each subject at each dispensing visit. Subjects continued on their pre-trial metformin dose. Any previous basal insulin analogue and OAD (oral anti-diabetes drug) treatments (except for metformin) were discontinued.
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 a minimum of 12 months prior to Visit 1 (screening) * Currently treated with a basal insulin analogue for at least 3 months prior to Visit 1 (screening) * Stable treatment (no change in dose or regimen) with a total daily dose of at least 1500 mg metformin or maximum tolerated dose (minimum 1000 mg) ± additional OAD treatment. The metformin treatment must have been stable for at least 2 months prior to Visit 1 (screening) * HbA1c higher or equal to 7.0% and below or equal to 10.0% (one re-test within one week of screening visit was allowed. The last sample was to be conclusive) * Body Mass Index (BMI) below or equal to 40.0 kg/m\^2 * Able and willing to eat at least 2 main meals each day during the trial * Able and willing to adhere to the protocol including compliance with performance of self measured plasma glucose (SMPG), injection regimen and titrating themselves according to the protocol * Experience in performing self measured plasma glucose (SMPG)
Exclusion criteria
* Treatment with any thiazolidinedione (TZD) and glucagon-like peptide-1 (GLP-1) receptor agonists or pramlintide within the last 3 months prior to Visit 1 (screening) * Impaired hepatic function defined as alanine aminotransferase (ALAT) above or equal to 2.5 times upper referenced limit (one re-test within one week of screening visit was allowed. The last sample was to be conclusive) * Impaired kidney function with serum creatinine above or equal to 133 micromol/L (1.5 mg/dL) for males and above or equal to 124 micromol/L (1.4 mg/dL) for females (one re-test within one week of screening visit was allowed. The last sample was to be conclusive) * Cardiac problems or uncontrolled treated/untreated severe hypertension (defined as systolic blood pressure higher or equal to 180 mmHg and/or diastolic blood pressure higher or equal to 100 mmHg) * Previous use of pre-mixed insulin products (pre-mixed insulin analogues or pre-mixed human preparations) or bolus insulin. Previous use of pre-mixed or bolus insulin products was allowed only in case of hospitalisation or a severe condition requiring intermittent use of pre-mixed or bolus insulin products for less than 14 consecutive days, but not during the last 3 months prior to screening visit (Visit 1)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (Glycosylated Haemoglobin) - FAS | Week 0, week 20 | Estimated mean change from baseline in HbA1c after 20 Weeks of treatment in full analysis set (FAS). |
| Change in HbA1c (Glycosylated Haemoglobin) - PP | Week 0, week 20 | Estimated mean change from baseline in HbA1c after 20 Weeks of treatment in per protocol (PP) analysis set. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) (Central Laboratory Values) | Week 0, week 20 | Estimated mean change from baseline in FPG after 20 Weeks of treatment |
| Number of Treatment Emergent Hypoglycaemic Episodes | Week 0 to week 20 | A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of trial product, and no later than one day after product administration. Severe hypoglycaemic episodes were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. |
| Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score | Week 0 | From the 20 TRIM-D items, an overall score was derived. The scores were transformed to a 0 - 100 scale with higher scores indicating a better health state. |
Countries
Argentina, China, India, Poland, Spain, United Kingdom
Participant flow
Recruitment details
A total of 33 sites in 5 countries enrolled subjects.
Participants by arm
| Arm | Count |
|---|---|
| Subject-driven The subjects performed the titration of biphasic insulin aspart 30 (BIAsp 30) dose and administered subcutaneously (under the skin) using FlexPen® twice daily for 20 weeks. The starting dose of BIAsp 30 was subject's previous basal insulin analogue dose split into two equal daily doses, immediately before breakfast and immediately before dinner. Directions for use were given to each subject at each dispensing visit. Subjects continued on their pre-trial metformin dose. Any previous basal insulin analogue and OAD (oral anti-diabetes drug) treatments (except for metformin) were discontinued. Metformin was allowed to be continued at the pre-trial dose with a total daily dose of at least 1500 mg or maximum tolerated dose (minimum 1000 mg) as prior to randomisation. | 174 |
| Investigator-driven The investigator performed the titration of biphasic insulin aspart 30 (BIAsp 30) dose and administered subcutaneously (under the skin) using FlexPen® twice daily for 20 weeks. The starting dose of BIAsp 30 was subject's previous basal insulin analogue dose split into two equal daily doses, immediately before breakfast and immediately before dinner. Directions for use were given to each subject at each dispensing visit. Subjects continued on their pre-trial metformin dose. Any previous basal insulin analogue and OAD (oral anti-diabetes drug) treatments (except for metformin) were discontinued. Metformin was allowed to be continued at the pre-trial dose with a total daily dose of at least 1500 mg or maximum tolerated dose (minimum 1000 mg) as prior to randomisation. | 174 |
| Total | 348 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Unclassified | 2 | 8 |
| Overall Study | Withdrawal Criteria | 4 | 4 |
Baseline characteristics
| Characteristic | Subject-driven | Investigator-driven | Total |
|---|---|---|---|
| Age, Continuous | 58.9 years STANDARD_DEVIATION 9.8 | 58.0 years STANDARD_DEVIATION 9.5 | 58.5 years STANDARD_DEVIATION 9.6 |
| Body Mass Index | 29.7 kg/m^2 STANDARD_DEVIATION 4.8 | 29.2 kg/m^2 STANDARD_DEVIATION 4.7 | 29.4 kg/m^2 STANDARD_DEVIATION 4.7 |
| Body Weight | 81.0 kg STANDARD_DEVIATION 16.2 | 78.0 kg STANDARD_DEVIATION 15 | 79.5 kg STANDARD_DEVIATION 15.7 |
| Fasting Plasma Glucose | 9.1 mmol/L STANDARD_DEVIATION 2.7 | 8.8 mmol/L STANDARD_DEVIATION 2.8 | 9.0 mmol/L STANDARD_DEVIATION 2.7 |
| Gender Female | 83 Participants | 87 Participants | 170 Participants |
| Gender Male | 91 Participants | 87 Participants | 178 Participants |
| Glycosylated Haemoglobin (HbA1c) | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 174 | 0 / 173 |
| serious Total, serious adverse events | 2 / 174 | 3 / 173 |
Outcome results
Primary
Change in HbA1c (Glycosylated Haemoglobin) - FAS
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) - analysis included endpoint derived after 20 Weeks of treatment and missing data was imputed using last observation carried forward (LOCF) where any post-baseline measurements were available. 13 subjects did not contribute to the statistical analysis after Week 20.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Subject-driven | Change in HbA1c (Glycosylated Haemoglobin) - FAS | -0.72 percentage of glycosylated haemoglobin | Standard Error 0.08 |
| Investigator-driven | Change in HbA1c (Glycosylated Haemoglobin) - FAS | -0.97 percentage of glycosylated haemoglobin | Standard Error 0.08 |
Comparison: FAS95% CI: [0.04, 0.46]Regression, Linear
Primary
Change in HbA1c (Glycosylated Haemoglobin) - PP
Estimated mean change from baseline in HbA1c after 20 Weeks of treatment in per protocol (PP) analysis set.
Time frame: Week 0, week 20
Population: Per protocol (PP) analysis set - analysis included subjects exposed to BIAsp 30 for more than 12 weeks without any major protocol violations. 24 subjects did not contribute to the statistical analysis after Week 20.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Subject-driven | Change in HbA1c (Glycosylated Haemoglobin) - PP | -0.71 percentage of glycosylated haemoglobin | Standard Error 0.08 |
| Investigator-driven | Change in HbA1c (Glycosylated Haemoglobin) - PP | -0.98 percentage of glycosylated haemoglobin | Standard Error 0.08 |
Comparison: PP95% CI: [0.05, 0.48]Regression, Linear
Secondary
Change in Fasting Plasma Glucose (FPG) (Central Laboratory Values)
Estimated mean change from baseline in FPG after 20 Weeks of treatment
Time frame: Week 0, week 20
Population: Full analysis set (FAS) - analysis included endpoint derived after 20 weeks of treatment and missing data was imputed using last observation carried forward (LOCF) where any post-baseline measurements were available. 13 subjects did not contribute to the statistical analysis after Week 20.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Subject-driven | Change in Fasting Plasma Glucose (FPG) (Central Laboratory Values) | -0.94 mmol/L | Standard Error 0.21 |
| Investigator-driven | Change in Fasting Plasma Glucose (FPG) (Central Laboratory Values) | -1.07 mmol/L | Standard Error 0.22 |
Comparison: H0: D = 0.0% against HA: D ≠ 0.0%, where D is the mean treatment difference (subject-driven titration minus investigator-driven titration).p-value: 0.65995% CI: [-0.44, 0.69]Regression, Linear
Secondary
Number of Treatment Emergent Hypoglycaemic Episodes
A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of trial product, and no later than one day after product administration. Severe hypoglycaemic episodes were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L.
Time frame: Week 0 to week 20
Population: Safety analysis set included all subjects who received at least one dose of BIAsp 30. One subject did not contribute to data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Subject-driven | Number of Treatment Emergent Hypoglycaemic Episodes | 638 episodes |
| Investigator-driven | Number of Treatment Emergent Hypoglycaemic Episodes | 766 episodes |
Secondary
Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score
From the 20 TRIM-D items, an overall score was derived. The scores were transformed to a 0 - 100 scale with higher scores indicating a better health state.
Time frame: Week 0
Population: Full analysis set (FAS) - analysis included endpoint derived after 20 weeks of treatment and missing data was imputed using last observation carried forward (LOCF) where any post-baseline measurements were available. 10 subjects did not contribute to data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subject-driven | Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score | 67.2 scores on a scale | Standard Deviation 14.7 |
| Investigator-driven | Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score | 70.0 scores on a scale | Standard Deviation 15.3 |
Secondary
Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score
From the 20 TRIM-D items, an overall score was derived. The scores were transformed to a 0 - 100 scale with higher scores indicating a better health state.
Time frame: Week 4
Population: Full analysis set (FAS) - analysis included endpoint derived after 20 weeks of treatment and missing data was imputed using last observation carried forward (LOCF) where any post-baseline measurements were available. 20 subjects did not contribute to data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subject-driven | Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score | 71.0 scores on a scale | Standard Deviation 13.1 |
| Investigator-driven | Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score | 71.8 scores on a scale | Standard Deviation 14.4 |
Secondary
Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score
From the 20 TRIM-D items, an overall score was derived. The scores were transformed to a 0 - 100 scale with higher scores indicating a better health state.
Time frame: Week 20
Population: Full analysis set (FAS) - analysis included endpoint derived after 20 weeks of treatment and missing data was imputed using last observation carried forward (LOCF) where any post-baseline measurements were available. 17 subjects did not contribute to data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subject-driven | Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score | 73.9 scores on a scale | Standard Deviation 13.6 |
| Investigator-driven | Patient Reported Outcomes Evaluated: Treatment-Related Impact Measures for Diabetes (TRIM-D) - Total Score | 74.0 scores on a scale | Standard Deviation 15.4 |