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Comparison of Insulin Detemir, Insulin Aspart and Biphasic Insulin Aspart 30 With OAD Treatment in Type 2 Diabetes (4T)

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ClinicalTrials.gov Identifier: NCT00184600
Recruitment Status : Completed
First Posted : September 16, 2005
Results First Posted : July 25, 2011
Last Update Posted : March 9, 2017
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Diabetes
Diabetes Mellitus, Type 2
Interventions Drug: biphasic insulin aspart
Drug: insulin detemir
Drug: insulin aspart
Enrollment 708
Recruitment Details 58 sites across the United Kingdom and Ireland. Recruitment period: November 2004-August 2006
Pre-assignment Details Eligible subjects continued their current oral anti-diabetic drug (OAD) treatment (metformin and/or sulphonylurea) without changing the dose throughout the trial. Subjects were asked not to alter their current diet and activities throughout the trial unless clinically necessary. Subjects fasted from 22:00 the evening prior to randomisation.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Period Title: Overall Study
Started 234 239 235
Completed 189 188 201
Not Completed 45 51 34
Reason Not Completed
Adverse Event             9             0             5
Death             3             9             7
Lack of Efficacy             3             1             3
Lost to Follow-up             4             6             1
Protocol Violation             2             2             3
Withdrawal by Subject             20             28             12
Unclassified             4             5             3
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin) Total
Hide Arm/Group Description Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen Total of all reporting groups
Overall Number of Baseline Participants 234 239 235 708
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 234 participants 239 participants 235 participants 708 participants
61.87  (9.97) 61.60  (10.54) 61.67  (8.93) 61.7  (9.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 234 participants 239 participants 235 participants 708 participants
Female
91
  38.9%
87
  36.4%
76
  32.3%
254
  35.9%
Male
143
  61.1%
152
  63.6%
159
  67.7%
454
  64.1%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 234 participants 239 participants 235 participants 708 participants
White 218 214 221 653
Mixed 2 4 1 7
Asian / Asian British 9 15 11 35
Black / Black British 2 5 2 9
Other 3 1 0 4
Smoking   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 234 participants 239 participants 235 participants 708 participants
Non Smoker, Never Smoked 106 88 82 276
Ex Smoker 95 108 120 323
Current Smoker 33 43 33 109
[1]
Measure Description: Identifying participants as smokers/non-smokers
Oral Anti-Diabetic Drugs (OADs)   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 234 participants 239 participants 235 participants 708 participants
Metformin 2 0 4 6
Sulphonylurea 8 12 10 30
Metformin + Sulphonylurea 224 227 221 672
[1]
Measure Description: Identifying which OAD (oral anti-diabetic drug) treatment the participant is on
Diabetic complication, Retinopathy   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 234 participants 239 participants 235 participants 708 participants
Yes 43 45 34 122
No 191 194 201 586
[1]
Measure Description: Diabetic complication at baseline
Diabetic complication, Neuropathy   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 234 participants 239 participants 235 participants 708 participants
Yes 39 55 41 135
No 195 184 194 573
[1]
Measure Description: Diabetic complication at baseline
Diabetic complication, Nephropathy   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 234 participants 239 participants 235 participants 708 participants
Yes 23 24 21 68
No 211 215 214 640
[1]
Measure Description: Diabetic complication at baseline
Diabetic complication, Macroaniopathy   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 234 participants 239 participants 235 participants 708 participants
Yes 44 42 52 138
No 190 197 183 570
[1]
Measure Description: Diabetic complication at baseline
Duration of diabetes   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 234 participants 239 participants 235 participants 708 participants
9
(6 to 12)
9
(6 to 14)
9
(6 to 12)
9
(6 to 13)
[1]
Measure Description: Number of years since diagnosis
Alcohol   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Units
Number Analyzed 234 participants 239 participants 235 participants 708 participants
4
(2 to 12)
5
(2 to 12)
6
(2 to 12)
5
(2 to 12)
[1]
Measure Description: Number of units consumed weekly. One unit of alcohol = 10ml pure alcohol by volume or 8g by weight.
Weight   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 234 participants 239 participants 235 participants 708 participants
85.52  (16.25) 84.92  (14.43) 86.91  (16.82) 85.8  (15.9)
[1]
Measure Description: Weight of participants
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 234 participants 239 participants 235 participants 708 participants
29.82  (4.59) 29.74  (4.51) 30.34  (4.73) 29.8  (4.6)
[1]
Measure Description: BMI of participants
Waist   [1] 
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 234 participants 239 participants 235 participants 708 participants
Men 104  (12) 102  (11) 104  (12) 103  (12)
Women 97  (12) 100  (11) 98  (13) 98  (12)
[1]
Measure Description: Waist circumference of participants
Eight-point Capillary Plasma Glucose Profiles  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 234 participants 239 participants 235 participants 708 participants
All time pointsexcluding 3 am 196  (43) 200  (49) 202  (47) 200  (47)
Fasting plasma 171  (47) 173  (49) 175  (50) 173  (49)
Postprandial 223  (50) 227  (56) 229  (54) 227  (54)
At 3 am 164  (56) 164  (59) 171  (58) 166  (58)
1.Primary Outcome
Title HbA1c (Glycosylated Haemoglobin) at Month 12
Hide Description HbA1c values offer evidence of the efficacy and durability of the insulin regimens.
Time Frame Baseline, Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Mean (Standard Deviation)
Unit of Measure: percentage (%) of total haemoglobin
Baseline 8.45  (0.80) 8.55  (0.78) 8.63  (0.81)
Month 12 7.64  (0.96) 7.20  (1.06) 7.33  (0.95)
2.Primary Outcome
Title HbA1c (Glycosylated Haemoglobin) at Month 36
Hide Description HbA1c values offer evidence of the efficacy and durability of the insulin regimens.
Time Frame Baseline, Month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Mean (Standard Deviation)
Unit of Measure: percentage (%) of total haemoglobin
Baseline 8.45  (0.80) 8.55  (0.78) 8.63  (0.81)
Month 36 7.11  (1.13) 7.04  (1.17) 7.22  (1.11)
3.Secondary Outcome
Title Percentage of Participants (Total Participants and the Subset of Participants Who Did Not Have an Hypoglycaemic Episode) Achieving a Month 12 Value in HbA1c Below or Equal to 6.5%
Hide Description Two participant counts are listed. The first is the percentage of total participants who achieved the target (HbA1c below or equal to 6.5%) at Month 12. The second is the percentage of subset of participants who achieved the target and did not have either minor or major hypoglycaemic episode within the four weeks prior to the month 12 exam. Minor hypoglycaemic episode is an episode in which the participant was able to treat her/himself and plasma glucose was below 3.1 mmol/L (56 mg/dL). Major hypoglycaemic episode is an episode in which the participant was unable to treat her/himself.
Time Frame Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Measure Type: Number
Unit of Measure: percentage of participants
Total participants who achieved target 8.1 23.9 17.0
Subset who achieved target, n=18, 50, 39 78.9 43.9 52.5
4.Secondary Outcome
Title Percentage of Participants Achieving a Month 36 Value in HbA1c Below or Equal to 6.5%
Hide Description Percentage of participants who achieved the target (HbA1c below or equal to 6.5%) at Month 36
Time Frame Month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Measure Type: Number
Unit of Measure: percentage of participants
43.2 44.8 31.9
5.Secondary Outcome
Title Number of Hypoglycaemic Events Per Participant Per Year at Month 12 for All Participants and the Subset Who Achieved Target HbA1c Below or Equal to 6.5%
Hide Description Rate of hypoglycaemic events was calculated as the median number of events per participant per year, defined as grade 1 (symptoms only), 2 (minor) and 3 (major). Symptoms only if self-measured plasma glucose level of 3.1 mmol/L (56 mg/dL) or more. Minor (grade 2) if able to treat her/himself and plasma glucose was below 3.1 mmol/L (56 mg/dL). Major (grade 3) if unable to treat her/himself. Rates are reported for all participants and for the subset of participants who achieved target HbA1c below or equal to 6.5%.
Time Frame Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Median (Inter-Quartile Range)
Unit of Measure: hypoglycaemic events/participant/year
All participants, Grade 1
2.0
(0.0 to 6.0)
8.0
(3.0 to 19.2)
5.0
(1.0 to 11.1)
All participants, Grade 2
0
(0 to 2.0)
8.0
(2.9 to 17.7)
3.9
(1.0 to 9.0)
All participants, Grade 3
0
(0 to 0)
0
(0 to 0)
0
(0 to 0)
All participants, Grade 2 or 3
0
(0 to 2.0)
8.0
(3.0 to 18.0)
3.9
(1.0 to 9.0)
Achieved HbA1c target, Grade 1, n=18, 50, 39
3.9
(0 to 5.2)
7.8
(2.0 to 21.0)
5.4
(1.5 to 12.8)
Achieved HbA1c target, Grade 2, n=18, 50, 39
3.0
(0 to 4.9)
8.0
(2.0 to 20.0)
4.0
(1.5 to 11.4)
Achieved HbA1c target, Grade 3, n=18, 50, 39
0
(0 to 0)
0
(0 to 0)
0
(0 to 0)
Achieved HbA1c target, Grade 2 or 3, n=18, 50, 39
3.0
(0 to 4.9)
8.7
(2.9 to 20.0)
4.0
(1.9 to 11.8)
6.Secondary Outcome
Title Number of Hypoglycaemic Events Per Participant Per Year at Month 36 for All Participants and the Subset Who Achieved Target HbA1c Below or Equal to 6.5%
Hide Description Rate of hypoglycaemic events was calculated as the median number of events per participant per year, defined as grade 1 (symptoms only), 2 (minor) and 3 (major). Symptoms only if self-measured plasma glucose level of 3.1 mmol/L (56 mg/dL) or more. Minor (grade 2) if able to treat her/himself and plasma glucose was below 3.1 mmol/L (56 mg/dL). Major (grade 3) if unable to treat her/himself. Rates are reported for all participants and for the subset of participants who achieved target HbA1c below or equal to 6.5%.
Time Frame Month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Median (Inter-Quartile Range)
Unit of Measure: hypoglycaemic events/participant/year
All participants, Grade 1
2.7
(2.3 to 3.0)
5.7
(4.3 to 7.2)
3.8
(3.3 to 4.3)
All participants, Grade 2
1.7
(1.3 to 2.0)
5.5
(4.3 to 6.9)
3.0
(2.3 to 4.0)
All participants, Grade 3
0
(0 to 0)
0
(0 to 0)
0
(0 to 0)
All participants, Grade 2 or 3
1.7
(1.3 to 2.0)
5.7
(4.3 to 7.0)
3.0
(2.3 to 4.0)
Achieved HbA1c target, Grade 1, n=73, 70, 55
3.0
(1.7 to 3.7)
5.7
(3.5 to 7.7)
3.0
(1.7 to 3.9)
Achieved HbA1c target, Grade 2, n=73, 70, 55
2.0
(1.3 to 2.7)
5.3
(3.8 to 8.0)
2.7
(1.7 to 5.2)
Achieved HbA1c target, Grade 3, n=73, 70, 55
0
(0 to 0)
0
(0 to 0)
0
(0 to 0)
Achieved HbA1c target, Grade 2 or 3, n=73, 70, 55
2.0
(1.3 to 2.7)
5.5
(4.0 to 8.0)
3.0
(1.7 to 5.3)
7.Secondary Outcome
Title Percentage of Participants Who Required A Second Insulin Therapy by Month 12
Hide Description Percentage of participants who required a second insulin formulation to be added to their treatment. This outcome offers evidence to the efficacy and durability of the insulin regimens.
Time Frame Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Measure Type: Number
Unit of Measure: percentage of participants
17.9 4.2 8.9
8.Secondary Outcome
Title Percentage of Participants Who Required A Second Insulin Therapy by Month 36
Hide Description Percentage of participants who required a second insulin formulation to be added to their treatment. This outcome offers evidence to the efficacy and durability of the insulin regimens.
Time Frame Month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Measure Type: Number
Unit of Measure: percentage of participants
89 82 88
9.Secondary Outcome
Title Change From Baseline in Body Weight at Month 12
Hide Description [Not Specified]
Time Frame Week 0 (baseline), month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Mean (Standard Deviation)
Unit of Measure: kilogram
1.9  (4.2) 5.7  (4.6) 4.7  (4.0)
10.Secondary Outcome
Title Change From Baseline in Body Weight at Month 36
Hide Description [Not Specified]
Time Frame Week 0 (baseline), month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Mean (Standard Deviation)
Unit of Measure: kilograms
3.6  (0.5) 6.4  (0.5) 5.7  (0.5)
11.Secondary Outcome
Title Change in Eight-point Capillary Plasma Glucose Profiles (Self-measured) at 12 Months
Hide Description For each visit and telephone contact, participants were asked to perform in advance three capillary glucose profiles (using blood glucose metre provided for the trial) obtained before breakfast and before the evening meal for participants in the biphasic and basal groups and before meals and two hours after meals and at bedtime in the prandial group.
Time Frame Baseline, month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Mean (Standard Deviation)
Unit of Measure: mg/dL
All timepoints excluding 3am -43  (43) -65  (43) -59  (54)
Fasting -59  (52) -23  (49) -45  (56)
Postprandial -47  (54) -83  (54) -68  (63)
3am -40  (70) -34  (59) -52  (70)
12.Secondary Outcome
Title Change in Eight-point Capillary Plasma Glucose Profiles (Self-measured) at 36 Months
Hide Description For each visit and telephone contact, participants were asked to perform in advance three capillary glucose profiles (using blood glucose metre provided for the trial) obtained before breakfast and before the evening meal for participants in the biphasic and basal groups and before meals and two hours after meals and at bedtime in the prandial group.
Time Frame Baseline, month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Mean (Standard Deviation)
Unit of Measure: mg/dL
All timepoints excluding 3am -58  (43) -67  (47) -56  (47)
Fasting -47  (49) -49  (45) -50  (47)
Postprandial -67  (50) -85  (59) -61  (58)
3am -45  (77) -27  (70) -38  (77)
13.Secondary Outcome
Title Quality of Life as Measured by the EuroQol Group 5-Dimension Self-Report Questionnaire Score (EQ5D) at 12 Months
Hide Description The EuroQol Group 5-Dimension Self-Report Questionnaire score (EQ5D) is a standardised instrument for use as a measure of health outcome in medical research. Responses can be used to generate a single numerical value associated with a given health state. The scale of values is graded from -0.59 to 1.00, with lower scores indicating a poorer health status. A score of 0 represents no quality of life and scores less than 0 represent states perceived by the respondent to be worse than death.
Time Frame Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.78
(0.75 to 0.81)
0.76
(0.73 to 0.79)
0.76
(0.73 to 0.80)
14.Secondary Outcome
Title Quality of Life as Measured by the EuroQol Group 5-Dimension Self-Report Questionnaire Score (EQ5D) at 36 Months
Hide Description The EuroQol Group 5-Dimension Self-Report Questionnaire score (EQ5D) is a standardised instrument for use as a measure of health outcome in medical research. Responses can be used to generate a single numerical value associated with a given health state. The scale of values is graded from -0.59 to 1.00, with lower scores indicating a poorer health status. A score of 0 represents no quality of life and scores less than 0 represent states perceived by the respondent to be worse than death.
Time Frame Month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analyses (ITT) included all those randomised. Missing data was imputed by SAS Proc MI (Multiple Imputation), using the non-parametric Propensity Score method for data with monotone missing pattern under the assumption of non-normality and the Bayesian Monte Carlo Markov Chain approach for data with values missing intermittently.
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description:
Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.80
(0.77 to 0.83)
0.77
(0.73 to 0.81)
0.76
(0.71 to 0.80)
15.Secondary Outcome
Title Number of Participants Having an 'Other' Adverse Event
Hide Description [Not Specified]
Time Frame Up to month 37 (36 months of treatment plus 1 month follow-up)
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Hide Analysis Population Description
Safety population consisting of all randomised participants exposed to at least one dose of trial drug(s).
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
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Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen
Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen
Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
Overall Number of Participants Analyzed 234 239 235
Measure Type: Number
Unit of Measure: participants
227 235 228
Time Frame The adverse events were collected from the first trial-related activity once the subject had signed the informed consent, up until 28 days after the last clinic visit. Total reporting period for adverse events was 162 weeks.
Adverse Event Reporting Description The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).
 
Arm/Group Title Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Hide Arm/Group Description Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. At week 24 and thereafter, if two consecutive measurements of HbA1c were at least 8%, or one measurement of HbA1c was at least 10% the subject was deemed to have unacceptable hyperglycaemia and a second insulin formulation was added. In the second and third years, a third insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen
All-Cause Mortality
Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   78/234 (33.33%)      79/239 (33.05%)      105/235 (44.68%)    
Blood and lymphatic system disorders       
Anaemia  1  1/234 (0.43%)  1 1/239 (0.42%)  1 1/235 (0.43%)  1
Iron deficiency anaemia  1  0/234 (0.00%)  0 1/239 (0.42%)  1 4/235 (1.70%)  4
Pernicious anaemia  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Cardiac disorders       
Acute coronary syndrome  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Acute left ventricular failure  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Acute myocardial infarction  1  2/234 (0.85%)  2 1/239 (0.42%)  1 2/235 (0.85%)  2
Angina pectoris  1  4/234 (1.71%)  5 2/239 (0.84%)  4 8/235 (3.40%)  11
Angina unstable  1  3/234 (1.28%)  3 1/239 (0.42%)  1 0/235 (0.00%)  0
Aortic valve incompetence  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Aortic valve stenosis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Arteriosclerosis coronary artery  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Atrial fibrillation  1  1/234 (0.43%)  2 1/239 (0.42%)  1 1/235 (0.43%)  2
Atrial flutter  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  2
Atrioventricular block  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Atrioventricular block complete  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Atrioventricular block second degree  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Bradycardia  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Cardiac arrest  1  1/234 (0.43%)  1 1/239 (0.42%)  1 0/235 (0.00%)  0
Cardiac failure  1  1/234 (0.43%)  1 3/239 (1.26%)  5 2/235 (0.85%)  2
Cardiac failure acute  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Cardiac failure congestive  1  3/234 (1.28%)  3 1/239 (0.42%)  1 4/235 (1.70%)  5
Coronary artery disease  1  0/234 (0.00%)  0 2/239 (0.84%)  2 2/235 (0.85%)  2
Coronary artery occlusion  1  0/234 (0.00%)  0 2/239 (0.84%)  2 0/235 (0.00%)  0
Coronary artery stenosis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Left ventribular dysfunction  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Left ventricular failure  1  2/234 (0.85%)  2 1/239 (0.42%)  1 2/235 (0.85%)  2
Myocardial infarction  1  6/234 (2.56%)  6 4/239 (1.67%)  4 2/235 (0.85%)  2
Myocardial ischaemia  1  1/234 (0.43%)  1 4/239 (1.67%)  4 2/235 (0.85%)  2
Palpitations  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Right ventricular failure  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Sinus bradycardia  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Tricuspid valve incompetence  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Endocrine disorders       
Goitre  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Eye disorders       
Cataract  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Diabetic retinopathy  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Eyelid ptosis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Optic ischaemic neuropathy  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Retinal detachment  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Vision blurred  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Gastrointestinal disorders       
Abdominal distension  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Abdominal pain  1  1/234 (0.43%)  2 1/239 (0.42%)  1 5/235 (2.13%)  5
Anal fissure  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Ascites  1  0/234 (0.00%)  0 0/239 (0.00%)  0 2/235 (0.85%)  2
Change of bowel habit  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Coeliac disease  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Colitis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Colitis ulcerative  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Constipation  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Crohn's disease  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Diarrhoea  1  1/234 (0.43%)  1 2/239 (0.84%)  2 2/235 (0.85%)  2
Diverticulum  1  0/234 (0.00%)  0 2/239 (0.84%)  3 1/235 (0.43%)  1
Duodenal ulcer  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Dyspepsia  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Epigastric discomfort  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Faeces discoloured  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Food poisoning  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Gastric ulcer  1  0/234 (0.00%)  0 0/239 (0.00%)  0 2/235 (0.85%)  2
Gastritis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Gastritis haemorrhagic  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Gastrointestinal haemorrhage  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Gastrooesophageal reflux disease  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Haematemesis  1  1/234 (0.43%)  1 0/239 (0.00%)  0 2/235 (0.85%)  2
Haematochezia  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Inguinal hernia  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Intestinal ischaemia  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Intestinal obstruction  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Melaena  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Nausea  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Oesophageal food impaction  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  2
Oesophageal rupture  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Oesophageal spasm  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Oesophageal ulcer  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Oesophagitis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Pancreatic pseudocyst  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Pancreatitis  1  1/234 (0.43%)  1 1/239 (0.42%)  1 2/235 (0.85%)  2
Pancreatitis chronic  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Pancreatolithiasis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Peptic ulcer  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Rectal haemorrhage  1  2/234 (0.85%)  2 0/239 (0.00%)  0 1/235 (0.43%)  1
Small intestinal haemorrhage  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Umbilical hernia  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Vomiting  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
General disorders       
Adverse drug reaction  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Asthenia  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Chest discomfort  1  0/234 (0.00%)  0 0/239 (0.00%)  0 2/235 (0.85%)  2
Chest pain  1  5/234 (2.14%)  5 1/239 (0.42%)  6 3/235 (1.28%)  3
Dislocation of joint prosthesis  1  1/234 (0.43%)  2 0/239 (0.00%)  0 0/235 (0.00%)  0
Gait disturbance  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Multi-organ failure  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Non-cardiac chest pain  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Oedema peripheral  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Pyrexia  1  1/234 (0.43%)  1 1/239 (0.42%)  1 0/235 (0.00%)  0
Hepatobiliary disorders       
Alcoholic liver disease  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  2
Cholecystitis  1  1/234 (0.43%)  1 1/239 (0.42%)  1 0/235 (0.00%)  0
Cholelithiasis  1  0/234 (0.00%)  0 2/239 (0.84%)  2 0/235 (0.00%)  0
Infections and infestations       
Abdominal abscess  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Abscess limb  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Anal abscess  1  2/234 (0.85%)  2 0/239 (0.00%)  0 0/235 (0.00%)  0
Biliary sepsis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Bronchiectasis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 2/235 (0.85%)  2
Bronchitis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Bronchpulmonary aspergillosis allergic  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Campylobacter gastroenteritis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Cellulitis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 6/235 (2.55%)  6
Cellulitis orbital  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Clostridial infection  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Clostridium difficile colitis  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Diverticulitis  1  0/234 (0.00%)  0 2/239 (0.84%)  2 0/235 (0.00%)  0
Gangrene  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Gastroenteritis  1  2/234 (0.85%)  2 0/239 (0.00%)  0 4/235 (1.70%)  4
Graft infection  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Infected skin ulcer  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Infective exacerbation of chronic obstructive airways  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Labyrinthitis  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Lobar pneumonia  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Localised infection  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Lower respiratory tract infection  1  0/234 (0.00%)  0 2/239 (0.84%)  2 3/235 (1.28%)  3
Nail infection  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Perineal abscess  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Pilonidal cyst  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Pneumonia  1  1/234 (0.43%)  1 1/239 (0.42%)  1 2/235 (0.85%)  2
Postoperative wound infection  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Pyelonephritis  1  0/234 (0.00%)  0 2/239 (0.84%)  2 0/235 (0.00%)  0
Respiratory tract infection  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Scrotal abscess  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Sepsis  1  2/234 (0.85%)  2 0/239 (0.00%)  0 2/235 (0.85%)  2
Staphylococcal osteomyelitis  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Stent related infection  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  2
Upper respiratory tract infection  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Urinary tract infection  1  1/234 (0.43%)  1 1/239 (0.42%)  1 3/235 (1.28%)  3
Wound infection  1  0/234 (0.00%)  0 2/239 (0.84%)  2 0/235 (0.00%)  0
Injury, poisoning and procedural complications       
Accidental overdose  1  3/234 (1.28%)  3 0/239 (0.00%)  0 0/235 (0.00%)  0
Ankle fracture  1  1/234 (0.43%)  1 1/239 (0.42%)  1 0/235 (0.00%)  0
Back injury  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Brain contusion  1  1/234 (0.43%)  2 0/239 (0.00%)  0 0/235 (0.00%)  0
Chest injury  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Drug dispensing error  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Fall  1  0/234 (0.00%)  0 2/239 (0.84%)  2 2/235 (0.85%)  2
Femoral neck fracture  1  1/234 (0.43%)  1 1/239 (0.42%)  1 3/235 (1.28%)  3
Head injury  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Hip fracture  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Incisional hernia  1  1/234 (0.43%)  1 1/239 (0.42%)  1 0/235 (0.00%)  0
Intentional overdose  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Joint injury  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Joint sprain  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Ligament rupture  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Medication error  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Meniscus lesion  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Post procedural complication  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Radius fracture  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Skull fracture base  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Subdural haemorrhage  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Tibia fracture  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Wrist fracture  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Wrong drug administered  1  2/234 (0.85%)  2 1/239 (0.42%)  1 0/235 (0.00%)  0
Investigations       
Biopsy liver  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Catheterisation cardiac  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
International normalised ratio increased  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Pulse absent  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Smear cervix abnormal  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Metabolism and nutrition disorders       
Dehydration  1  1/234 (0.43%)  1 1/239 (0.42%)  1 0/235 (0.00%)  0
Diabetes mellitus inadequate control  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Fluid retention  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Hypoglycaemia  1  5/234 (2.14%)  7 13/239 (5.44%)  13 12/235 (5.11%)  14
Hypoglycaemic unconsciousness  1  3/234 (1.28%)  3 0/239 (0.00%)  0 1/235 (0.43%)  1
Musculoskeletal and connective tissue disorders       
Arthralgia  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Arthritis  1  1/234 (0.43%)  1 1/239 (0.42%)  1 0/235 (0.00%)  0
Back pain  1  0/234 (0.00%)  0 0/239 (0.00%)  0 2/235 (0.85%)  2
Dupuytren's contracture operation  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Foot deformity  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Groin pain  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Haemarthrosis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Intervertebral disc compression  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Intervertebral disc protrusion  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Lower extremity mass  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Muscle haemorrhage  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Muscular weakness  1  0/234 (0.00%)  0 0/239 (0.00%)  0 2/235 (0.85%)  2
Musculoskeletal chest pain  1  1/234 (0.43%)  1 2/239 (0.84%)  2 0/235 (0.00%)  0
Musculoskeletal pain  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Neuropathic arthropathy  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Osteoarthritis  1  4/234 (1.71%)  4 1/239 (0.42%)  1 6/235 (2.55%)  7
Osteoporosis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Pain in extremity  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Periarthritis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Polymyalgia rheumatica  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Rheumatoid arthritis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Synovitis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Adenocarcinoma pancreas  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Basal cell carcinoma  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Basosquamous carcinoma  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Benign breast neoplasm  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Bladder papilloma  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Bladder transitional cell carcinoma  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Borderline ovarian tumour  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Colon cancer  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Colon cancer stage I  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Endometrial cancer  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Endometrial cancer stage III  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Galbladder cancer  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Hepatic neoplasm malignant recurrent  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Laryngeal cancer  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Leiomyosarcoma metastatic  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Lung neoplasm malignant  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Metastases to liver  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Metastases to lung  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Metastatic neoplasm  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Non-small cell lung cancer metastatic  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Non-small cell lung cancer stage IIIB  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Pancreatic carcinoma  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Prostate cancer  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Rectal cancer metastatic  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Rectal cancer stage III  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Transitional cell carcinoma  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Nervous system disorders       
Carotid artery occlusion  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Carotid artery stenosis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Carpal tunnel syndrome  1  0/234 (0.00%)  0 1/239 (0.42%)  1 3/235 (1.28%)  3
Cerebral haemorrhage  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Cerebral infarction  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Cerebrovascular accident  1  2/234 (0.85%)  2 0/239 (0.00%)  0 3/235 (1.28%)  3
Cognitive disorder  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Dizziness  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Hypoglycaemic coma  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Lacunar infarction  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Loss of consciousness  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Neuropathy peripheral  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Paraesthesia  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Pneumocephalus  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Presyncope  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Radiculitis brachial  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Sensory loss  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Spinal cord compression  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Subarachnoid haemorrhage  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Transient ischaemic attack  1  0/234 (0.00%)  0 1/239 (0.42%)  1 2/235 (0.85%)  2
Psychiatric disorders       
Anxiety  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Anxiety disorder  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Confusional state  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Depression  1  1/234 (0.43%)  1 0/239 (0.00%)  0 1/235 (0.43%)  1
Panic attack  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Renal and urinary disorders       
Calculus ureteric  1  0/234 (0.00%)  0 0/239 (0.00%)  0 2/235 (0.85%)  2
Dysuria  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Haematuria  1  0/234 (0.00%)  0 2/239 (0.84%)  2 1/235 (0.43%)  1
Nephrolithiasis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Renal colic  1  0/234 (0.00%)  0 1/239 (0.42%)  1 2/235 (0.85%)  2
Renal failure  1  0/234 (0.00%)  0 2/239 (0.84%)  2 0/235 (0.00%)  0
Renal failure acute  1  0/234 (0.00%)  0 2/239 (0.84%)  2 0/235 (0.00%)  0
Renal failure chronic  1  0/234 (0.00%)  0 1/239 (0.42%)  2 0/235 (0.00%)  0
Renal impairment  1  1/234 (0.43%)  1 1/239 (0.42%)  1 2/235 (0.85%)  2
Urethral meatus stenosis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Urethral stenosis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Urinary retention  1  1/234 (0.43%)  1 1/239 (0.42%)  1 2/235 (0.85%)  2
Reproductive system and breast disorders       
Benign prostatic hyperplasia  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Haematospermia  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Ovarian cyst  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Prostatomegaly  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Vaginal haemorrhage  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Respiratory, thoracic and mediastinal disorders       
Acute pulmonary oedema  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Asthma  1  2/234 (0.85%)  3 1/239 (0.42%)  1 0/235 (0.00%)  0
Chronic obstructive pulmonary disease  1  1/234 (0.43%)  1 2/239 (0.84%)  2 1/235 (0.43%)  1
Dysphonia  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Dyspnoea  1  3/234 (1.28%)  3 3/239 (1.26%)  3 3/235 (1.28%)  3
Epistaxis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 2/235 (0.85%)  2
Pleural effusion  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Pulmonary embolism  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Pulmonary oedema  1  3/234 (1.28%)  3 2/239 (0.84%)  2 0/235 (0.00%)  0
Respiratory failure  1  0/234 (0.00%)  0 0/239 (0.00%)  0 2/235 (0.85%)  2
Sleep apnoea syndrome  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Wegener's granulomatosis  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Skin and subcutaneous tissue disorders       
Angioedema  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Ingrowing nail  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Lichen sclerosus  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  4
Pruritis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Skin ulcer  1  2/234 (0.85%)  2 0/239 (0.00%)  0 0/235 (0.00%)  0
Surgical and medical procedures       
Knee arthroplasty  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Penile prosthesis insertion  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Umbilical hernia repair  1  0/234 (0.00%)  0 1/239 (0.42%)  1 0/235 (0.00%)  0
Vascular disorders       
Arterial stenosis limb  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Circulatory collapse  1  0/234 (0.00%)  0 4/239 (1.67%)  4 0/235 (0.00%)  0
Deep vein thrombosis  1  0/234 (0.00%)  0 1/239 (0.42%)  1 1/235 (0.43%)  1
Femoral arterial stenosis  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Femoral artery occlusion  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Haematoma  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Hypotension  1  0/234 (0.00%)  0 2/239 (0.84%)  2 0/235 (0.00%)  0
Intermittent claudication  1  2/234 (0.85%)  2 2/239 (0.84%)  2 0/235 (0.00%)  0
Ischaemia  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Peripheral vascular disorder  1  1/234 (0.43%)  1 1/239 (0.42%)  3 0/235 (0.00%)  0
Varicose vein  1  1/234 (0.43%)  1 0/239 (0.00%)  0 0/235 (0.00%)  0
Vasculitis  1  0/234 (0.00%)  0 0/239 (0.00%)  0 1/235 (0.43%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA Unspecified
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Insulin Detemir (Basal Insulin) Insulin Aspart (Prandial Insulin) Biphasic Insulin Aspart 30 (Biphasic Insulin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   227/234 (97.01%)      235/239 (98.33%)      228/235 (97.02%)    
Blood and lymphatic system disorders       
Anaemia  1  19/234 (8.12%)  19 13/239 (5.44%)  14 14/235 (5.96%)  16
Eye disorders       
Diabetic retinopathy  1  19/234 (8.12%)  20 10/239 (4.18%)  10 4/235 (1.70%)  4
Gastrointestinal disorders       
Abdominal discomfort  1  14/234 (5.98%)  33 16/239 (6.69%)  24 27/235 (11.49%)  40
Abdominal pain  1  9/234 (3.85%)  12 7/239 (2.93%)  7 14/235 (5.96%)  20
Diarrhoea  1  60/234 (25.64%)  115 53/239 (22.18%)  75 45/235 (19.15%)  63
Dyspepsia  1  21/234 (8.97%)  38 14/239 (5.86%)  15 13/235 (5.53%)  19
Vomiting  1  45/234 (19.23%)  80 44/239 (18.41%)  68 43/235 (18.30%)  71
General disorders       
Fatigue  1  12/234 (5.13%)  15 10/239 (4.18%)  12 4/235 (1.70%)  7
Injection site haematoma  1  39/234 (16.67%)  49 34/239 (14.23%)  50 34/235 (14.47%)  46
Injection site mass  1  18/234 (7.69%)  23 7/239 (2.93%)  7 16/235 (6.81%)  21
Malaise  1  15/234 (6.41%)  38 18/239 (7.53%)  38 18/235 (7.66%)  27
Infections and infestations       
Bronchitis  1  12/234 (5.13%)  17 10/239 (4.18%)  13 6/235 (2.55%)  17
Ear infection  1  6/234 (2.56%)  8 11/239 (4.60%)  15 17/235 (7.23%)  17
Gastroenteritis  1  10/234 (4.27%)  13 8/239 (3.35%)  12 14/235 (5.96%)  15
Infection  1  50/234 (21.37%)  84 55/239 (23.01%)  88 59/235 (25.11%)  89
Influenza  1  37/234 (15.81%)  55 29/239 (12.13%)  33 33/235 (14.04%)  43
Localised infection  1  9/234 (3.85%)  13 12/239 (5.02%)  14 16/235 (6.81%)  20
Nasopharyngitis  1  108/234 (46.15%)  251 97/239 (40.59%)  211 99/235 (42.13%)  208
Pharyngitis  1  13/234 (5.56%)  17 8/239 (3.35%)  8 7/235 (2.98%)  9
Upper respiratory tract infection  1  33/234 (14.10%)  51 28/239 (11.72%)  51 27/235 (11.49%)  35
Urinary tract infection  1  32/234 (13.68%)  67 24/239 (10.04%)  31 30/235 (12.77%)  60
Viral infection  1  12/234 (5.13%)  12 10/239 (4.18%)  13 13/235 (5.53%)  17
Injury, poisoning and procedural complications       
Fall  1  20/234 (8.55%)  24 20/239 (8.37%)  23 16/235 (6.81%)  20
Musculoskeletal and connective tissue disorders       
Arthralgia  1  15/234 (6.41%)  16 23/239 (9.62%)  32 25/235 (10.64%)  32
Back pain  1  31/234 (13.25%)  40 38/239 (15.90%)  42 28/235 (11.91%)  35
Joint swelling  1  14/234 (5.98%)  15 14/239 (5.86%)  14 8/235 (3.40%)  8
Muscle spasms  1  11/234 (4.70%)  14 13/239 (5.44%)  15 7/235 (2.98%)  11
Pain in extremity  1  30/234 (12.82%)  37 31/239 (12.97%)  35 36/235 (15.32%)  41
Nervous system disorders       
Dizziness  1  20/234 (8.55%)  28 16/239 (6.69%)  23 15/235 (6.38%)  17
Paraesthesia  1  13/234 (5.56%)  13 11/239 (4.60%)  16 13/235 (5.53%)  18
Psychiatric disorders       
Depression  1  8/234 (3.42%)  10 12/239 (5.02%)  12 16/235 (6.81%)  16
Respiratory, thoracic and mediastinal disorders       
Cough  1  48/234 (20.51%)  66 51/239 (21.34%)  63 38/235 (16.17%)  46
Dyspnoea  1  13/234 (5.56%)  15 20/239 (8.37%)  24 13/235 (5.53%)  14
Oropharyngeal pain  1  35/234 (14.96%)  51 31/239 (12.97%)  55 27/235 (11.49%)  37
Skin and subcutaneous tissue disorders       
Rash  1  11/234 (4.70%)  14 12/239 (5.02%)  12 14/235 (5.96%)  14
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA Unspecified
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Novo Nordisk reserves the right to not release data until specified milestones are reached. This includes the right to not release interim results of clinical trials, because that can invalidate results of the entire trial. At the end of the trial, one or more manuscripts for publication will be prepared collaboratively between Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for less than 60 days to protect intellectual property.
Results Point of Contact
Name/Title: Public Access to Clinical Trials
Organization: Novo Nordisk A/S
Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT00184600     History of Changes
Other Study ID Numbers: NN304-1613
2004-000514-38 ( EudraCT Number )
First Submitted: September 13, 2005
First Posted: September 16, 2005
Results First Submitted: May 10, 2011
Results First Posted: July 25, 2011
Last Update Posted: March 9, 2017