Trial Outcomes & Findings for Comparing Efficacy and Safety of Thrice Daily Versus Twice Daily NovoMix® 30 (Biphasic Insulin Aspart 30) in Subjects With Type 2 Diabetes Inadequately Controlled With Basal Insulin (NCT NCT02582242)

Last Updated: 2019-06-11

Results Overview

Change from baseline in HbA1c was evaluated after 24 weeks of treatment. Missing data was imputed using the last observation carried forward (LOCF) method.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

437 participants

Primary outcome timeframe

Week 0, Week 24

Results posted on

2019-06-11

Participant Flow

A total of 50 sites were approved for recruiting subjects, of which 48 sites (in 2 regions) screened and randomized the subjects (China region, including mainland China, Hong Kong and Taiwan; non-China region, including other 4 countries) as follows: Algeria: 3; mainland China: 23; Hong Kong: 1; India: 8; Taiwan: 4; Turkey: 5; Ukraine: 4.

Participant milestones

Participant milestones
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) Subjects received biphasic insulin aspart 30 (BIAsp 30; a mixture of soluble insulin aspart \[IAsp\] 30% and protaminated IAsp 70%) three times daily (TID); before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as subcutaneous (s.c.; under the skin) injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal self-measured plasma glucose (SMPG) target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) Subjects received BIAsp 30 twice daily (BID); before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Overall Study STARTED	220	217
Overall Study COMPLETED	200	200
Overall Study NOT COMPLETED	20	17

Reasons for withdrawal

Reasons for withdrawal
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) Subjects received biphasic insulin aspart 30 (BIAsp 30; a mixture of soluble insulin aspart \[IAsp\] 30% and protaminated IAsp 70%) three times daily (TID); before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as subcutaneous (s.c.; under the skin) injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal self-measured plasma glucose (SMPG) target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) Subjects received BIAsp 30 twice daily (BID); before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Overall Study Adverse Event	4	3
Overall Study Protocol Violation	3	1
Overall Study Lost to Follow-up	0	1
Overall Study Withdrawal by Subject	11	11
Overall Study Unclassified	2	1

Baseline Characteristics

Comparing Efficacy and Safety of Thrice Daily Versus Twice Daily NovoMix® 30 (Biphasic Insulin Aspart 30) in Subjects With Type 2 Diabetes Inadequately Controlled With Basal Insulin

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Total n=437 Participants Total of all reporting groups
Age, Continuous	57.0 years STANDARD_DEVIATION 9.8 • n=5 Participants	56.6 years STANDARD_DEVIATION 9.3 • n=7 Participants	56.8 years STANDARD_DEVIATION 9.5 • n=5 Participants
Sex: Female, Male Female	112 Participants n=5 Participants	108 Participants n=7 Participants	220 Participants n=5 Participants
Sex: Female, Male Male	108 Participants n=5 Participants	109 Participants n=7 Participants	217 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	218 Participants n=5 Participants	217 Participants n=7 Participants	435 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	181 Participants n=5 Participants	170 Participants n=7 Participants	351 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	39 Participants n=5 Participants	47 Participants n=7 Participants	86 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Glycosylated haemoglobin (HbA1c)	8.74 Percentage of HbA1c STANDARD_DEVIATION 0.69 • n=5 Participants	8.68 Percentage of HbA1c STANDARD_DEVIATION 0.69 • n=7 Participants	8.71 Percentage of HbA1c STANDARD_DEVIATION 0.69 • n=5 Participants
Fasting plasma glucose (FPG)	8.68 mmol/L STANDARD_DEVIATION 2.68 • n=5 Participants	8.72 mmol/L STANDARD_DEVIATION 2.39 • n=7 Participants	8.70 mmol/L STANDARD_DEVIATION 2.54 • n=5 Participants
Body weight	71.57 kg STANDARD_DEVIATION 13.38 • n=5 Participants	72.24 kg STANDARD_DEVIATION 13.01 • n=7 Participants	71.90 kg STANDARD_DEVIATION 13.19 • n=5 Participants

PRIMARY outcome

Timeframe: Week 0, Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data.

Change from baseline in HbA1c was evaluated after 24 weeks of treatment. Missing data was imputed using the last observation carried forward (LOCF) method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Change in Glycosylated Haemoglobin (HbA1c)	-1.66 Percentage (%) of HbA1c Standard Deviation 1.00	-1.52 Percentage (%) of HbA1c Standard Deviation 0.94

SECONDARY outcome

Timeframe: Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data.

Percentage of subjects achieving HbA1c \<7.0% (yes or no) was evaluated after 24 weeks of treatment.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Proportion of Subjects Achieving HbA1c Below 7.0% Yes	54.5 Percentage (%) of participants	47.5 Percentage (%) of participants
Proportion of Subjects Achieving HbA1c Below 7.0% No	45.5 Percentage (%) of participants	52.5 Percentage (%) of participants

SECONDARY outcome

Timeframe: Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data.

Percentage of subjects achieving HbA1c \<7.0% (yes or no) without severe hypoglycaemic episodes was evaluated after 24 weeks of treatment. Severe hypoglycaemia: Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose (PG) concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes. Yes	50.0 Percentage (%) of participants	44.7 Percentage (%) of participants
Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes. No	50.0 Percentage (%) of participants	55.3 Percentage (%) of participants

SECONDARY outcome

Timeframe: Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data.

Percentage of subjects achieving HbA1c \<7.0% (yes or no) without severe or BG confirmed hypoglycaemic episodes (according to the Novo Nordisk classification) was evaluated after 24 weeks of treatment. Severe or BG confirmed hypoglycaemia: an episode that is severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose (PG) value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. Severe hypoglycaemia as per ADA: Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification) Yes	27.3 Percentage (%) of participants	21.7 Percentage (%) of participants
Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification) No	72.7 Percentage (%) of participants	78.3 Percentage (%) of participants

SECONDARY outcome

Timeframe: Week 0-24

Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30). Treatment emergent hypoglycaemic episodes were defined as the hypoglycaemic episodes, which occurred on or after the first day of trial product administration (in week 0), and no later than 7 days after the last day on trial product.

ADA classification of hypoglycaemia: 1. Severe:Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be available during event, but neurological recovery following return of PG to normal is considered sufficient evidence that the event was induced by low PG concentration 2. Asymptomatic:Episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L 3. Documented symptomatic:Episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤3.9 mmol/L 4. Pseudo:Episode during which person with diabetes reports any of the typical symptoms of hypoglycaemia with measured PG concentration \>3.9 mmol/L but approaching that level 5. Probable symptomatic:Episode during which symptoms of hypoglycaemia are not accompanied by PG determination but that was presumably caused by a PG concentration ≤3.9 mmol/L

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition Severe	3 Count of hypoglycaemic episodes	3 Count of hypoglycaemic episodes
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition Asymptomatic	397 Count of hypoglycaemic episodes	344 Count of hypoglycaemic episodes
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition Documented symptomatic	642 Count of hypoglycaemic episodes	765 Count of hypoglycaemic episodes
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition Pseudo-hypoglycaemia	54 Count of hypoglycaemic episodes	93 Count of hypoglycaemic episodes
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition Probable symptomatic	61 Count of hypoglycaemic episodes	30 Count of hypoglycaemic episodes

SECONDARY outcome

Timeframe: Week 0-24

Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30).

Treatment emergent hypoglycaemic episodes were defined as the hypoglycaemic episodes, which occurred on or after the first day of trial product administration (in week 0), and no later than 7 days after the last day on trial product. Novo Nordisk (NN) classification of hypoglycaemia: 1. Severe hypoglycaemia: According to the ADA classification. 2. Blood glucose (BG) confirmed hypoglycaemia: an episode that is BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 3. Severe or BG confirmed hypoglycaemia: an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition Severe	3 Count of hypoglycaemic episodes	3 Count of hypoglycaemic episodes
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition BG confirmed	249 Count of hypoglycaemic episodes	249 Count of hypoglycaemic episodes
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition Severe or BG confirmed	252 Count of hypoglycaemic episodes	252 Count of hypoglycaemic episodes
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition Severe or BG confirmed symptomatic	195 Count of hypoglycaemic episodes	223 Count of hypoglycaemic episodes
Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition NN unclassifiable	905 Count of hypoglycaemic episodes	983 Count of hypoglycaemic episodes

SECONDARY outcome

Timeframe: Week 0, Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at the specified time point.

Change from baseline in fasting plasma glucose (FPG) by central laboratory analysis was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Change From Baseline in FPG by Central Laboratory Analysis	-1.34 mmol/L Standard Deviation 3.10	-1.07 mmol/L Standard Deviation 2.64

SECONDARY outcome

Timeframe: Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at specified time points.

7-point self-measured plasma glucose (SMPG) profiles was evaluated after 24 weeks of treatment. Subjects were instructed to perform the following SMPG measurements: 1. Before breakfast. 2. 120 minutes after the start of breakfast. 3. Before lunch. 4. 120 minutes after the start of lunch. 5. Before main evening meal. 6. 120 minutes after the start of main evening meal. 7. At bedtime. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
7-point SMPG Profile Before breakfast	6.87 mmol/L Standard Deviation 1.61	6.86 mmol/L Standard Deviation 1.71
7-point SMPG Profile 120 minutes after start of breakfast	9.33 mmol/L Standard Deviation 3.14	9.04 mmol/L Standard Deviation 3.20
7-point SMPG Profile Before lunch	6.86 mmol/L Standard Deviation 2.21	7.09 mmol/L Standard Deviation 2.72
7-point SMPG Profile 120 minutes after start of lunch	9.48 mmol/L Standard Deviation 3.02	9.92 mmol/L Standard Deviation 3.54
7-point SMPG Profile Before main evening meal	7.26 mmol/L Standard Deviation 2.08	7.68 mmol/L Standard Deviation 2.53
7-point SMPG Profile 120 minutes after start of main evening meal	8.77 mmol/L Standard Deviation 3.00	9.09 mmol/L Standard Deviation 3.29
7-point SMPG Profile At bedtime	7.69 mmol/L Standard Deviation 2.50	8.24 mmol/L Standard Deviation 3.15

SECONDARY outcome

Timeframe: Week 0, Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at specified time points.

Change from baseline in 2-hour postprandial glucose (PPG) at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) Change in PPG breakfast	-4.17 mmol/L Standard Deviation 4.84	-4.03 mmol/L Standard Deviation 4.22
7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) Change in PPG lunch	-3.43 mmol/L Standard Deviation 4.56	-3.27 mmol/L Standard Deviation 4.59
7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) Change in PPG main evening meal	-4.38 mmol/L Standard Deviation 4.44	-4.09 mmol/L Standard Deviation 4.71

SECONDARY outcome

Timeframe: Week 0, Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at specified time points.

Change from baseline in PPG increment at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) Change in PPG increment breakfast	-2.06 mmol/L Standard Deviation 4.44	-2.02 mmol/L Standard Deviation 3.95
7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) Change in PPG increment lunch	-0.13 mmol/L Standard Deviation 4.38	-0.14 mmol/L Standard Deviation 4.40
7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) Change in PPG increment main evening meal	-0.64 mmol/L Standard Deviation 4.55	-1.60 mmol/L Standard Deviation 4.72

SECONDARY outcome

Timeframe: Week 0, Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at the specified time point.

Change from baseline in mean of 2-hour PPG at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
7-point SMPG Profiles: Change From Baseline in Mean of 2-hour PPG Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal)	-3.98 mmol/L Standard Deviation 3.59	-3.77 mmol/L Standard Deviation 3.48

SECONDARY outcome

Timeframe: Week 0, Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data.

Change from baseline in mean of PPG increment at individual meal (breakfast, lunch and main evening meal) was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
7-point SMPG Profiles: Change From Baseline in Mean of PPG Increment Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal)	-0.96 mmol/L Standard Deviation 2.53	-1.22 mmol/L Standard Deviation 2.68

SECONDARY outcome

Timeframe: Week 0, Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at the specified time point.

Change from baseline in mean of the 7-point SMPG profiles was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
7-point SMPG Profiles: Change From Baseline in Mean of the 7-point Profile	-3.58 mmol/L Standard Deviation 3.08	-3.27 mmol/L Standard Deviation 2.84

SECONDARY outcome

Timeframe: Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data. Number analyzed = number of subjects contributed to the evaluation at the specified time point.

Fluctuation in the 7-point SMPG profile was evaluated after 24 weeks of treatment. Fluctuation in 7-point SMPG profile was the average absolute difference to the mean of the profile of the 7-point SMPG measurements accumulated over the profile. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
7-point SMPG Profiles: Fluctuation in the 7-point Profile	1.04 mmol/L Geometric Coefficient of Variation 54.04	1.05 mmol/L Geometric Coefficient of Variation 54.39

SECONDARY outcome

Timeframe: Week 0-24

Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30). Number analyzed = number of subjects with corresponding numbers of TEAEs.

Incidence of TEAEs was recorded during 24 weeks of treatment. A TEAE was defined as an event that has onset date (or increase in severity) on or after the first day of exposure to trial product (in week 0) and no later than 7 days after the last day on trial product.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Incidence of Treatment Emergent Adverse Events (TEAEs)	275 Number of adverse events	251 Number of adverse events

SECONDARY outcome

Timeframe: Week 1, Week 24

Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30). Number analyzed = number of subjects contributed to the evaluation at the specified time point.

Total daily insulin dose was the sum of doses given before breakfast and before main evening meal for the BID treatment group, and the sum of doses given before breakfast, before lunch and before main evening meal for the TID treatment group. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Total Daily Insulin Dose Week 1	24.5 Units (U) Standard Deviation 10.0	24.2 Units (U) Standard Deviation 13.0
Total Daily Insulin Dose Week 24	67.4 Units (U) Standard Deviation 35.5	63.4 Units (U) Standard Deviation 33.1

SECONDARY outcome

Timeframe: Week 0, Week 24

Population: Safety analysis set included all subjects who received at least one dose of investigational product (BIAsp 30).

Change from baseline in body weight was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Change From Baseline in Body Weight	1.45 Kilogram (kg) Standard Deviation 3.11	1.65 Kilogram (kg) Standard Deviation 2.85

SECONDARY outcome

Timeframe: Week 0, Week 24

Population: FAS included all randomised subjects who were dosed and had any post randomisation data.

Change from baseline in patient-reported treatment satisfaction (as assessed by the DTSQs) was evaluated after 24 weeks of treatment. The DTSQs is a self-completion questionnaire used to investigate the subject's treatment satisfaction. The DTSQ contained 8 questions, which were scored on a scale from 0 to 6. Out of 8 questions, 6 were related to the overall treatment satisfaction and 2 were related to glycaemic control (hypoglycaemia and hyperglycaemia). Results for the 6 questions relating to overall treatment satisfaction are presented together whereas the 2 questions relating to blood glucose are presented separately. For the overall treatment satisfaction, a higher score (0-36) was related to a better perception of treatment satisfaction. For hypoglycaemia and hyperglycaemia, a lower score (0-6) was related to a better blood glucose control. Missing data was imputed using the LOCF method.

Outcome measures

Outcome measures
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 Participants Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 Participants Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) Overall treatment satisfaction	2 Score on a scale Interval -29.0 to 24.0	4 Score on a scale Interval -21.0 to 29.0
Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) Hypoglycaemia	0 Score on a scale Interval -6.0 to 6.0	0 Score on a scale Interval -5.0 to 6.0
Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) Hyperglycaemia	-1 Score on a scale Interval -6.0 to 4.0	-1 Score on a scale Interval -6.0 to 5.0

Adverse Events

Biphasic Insulin Aspart 30 (Three Times Daily)

Serious events: 12 serious events

Other events: 34 other events

Deaths: 0 deaths

Biphasic Insulin Aspart 30 (Twice Daily)

Serious events: 9 serious events

Other events: 36 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 participants at risk Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 participants at risk Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Nervous system disorders Headache	4.5% 10/220 • Number of events 16 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	5.1% 11/217 • Number of events 13 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Infections and infestations Upper respiratory tract infection	11.8% 26/220 • Number of events 31 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	12.4% 27/217 • Number of events 32 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).

Additional Information

Clinical Reporting Anchor and Disclosure (1452)

Novo Nordisk A/S

Phone: (+1) 866-867-7178

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee At the end of the trial, one or more scientific publications may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.
Publication restrictions are in place

Restriction type: OTHER

Measure	Biphasic Insulin Aspart 30 (Three Times Daily) n=220 participants at risk Subjects received BIAsp 30 TID; before breakfast, lunch and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.	Biphasic Insulin Aspart 30 (Twice Daily) n=217 participants at risk Subjects received BIAsp 30 BID; before breakfast and main evening meal for a duration of 24-week. BIAsp 30 was administered as s.c. injection according to the locally approved label and as described in the direction for use. The total daily dose of pre-trial basal insulin was transferred to the total daily starting dose of BIAsp 30 by unit-to-unit, which was distributed along meals at the investigator's discretion. During the 24-week treatment period, the insulin dose was individually titrated on a weekly basis for all subjects in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Subjects continued with their stable, pre-trial dose of metformin (a total daily oral dose of \>=1500 mg metformin or maximum tolerated dose) throughout the entire treatment period.
Cardiac disorders Acute coronary syndrome	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Blood and lymphatic system disorders Anaemia	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Cardiac disorders Angina unstable	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Nervous system disorders Cerebral infarction	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Cardiac disorders Coronary artery disease	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.92% 2/217 • Number of events 2 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Injury, poisoning and procedural complications Craniocerebral injury	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Skin and subcutaneous tissue disorders Diabetic foot	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Renal and urinary disorders Diabetic nephropathy	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Nervous system disorders Diabetic neuropathy	0.91% 2/220 • Number of events 2 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Eye disorders Diabetic retinopathy	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Nervous system disorders Hypoglycaemic seizure	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Gastrointestinal disorders Intestinal polyp	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Injury, poisoning and procedural complications Laceration	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Nervous system disorders Lacunar infarction	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Cardiac disorders Mitral valve incompetence	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
General disorders Oedema	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Infections and infestations Pneumonia	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Injury, poisoning and procedural complications Rib fracture	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Injury, poisoning and procedural complications Soft tissue injury	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Musculoskeletal and connective tissue disorders Trigger finger	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Eye disorders Vitreous haemorrhage	0.00% 0/220 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.46% 1/217 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Infections and infestations Wound infection	0.45% 1/220 • Number of events 1 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).	0.00% 0/217 • Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs. Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).