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

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02582242
• Collaborator: (none)
• Enrollment: 437
• Locations: 50
• Arms: 2
• Actual Duration (Months): 18
• Patients Per Site: 8.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This trial is conducted in Asia. The aim of the trial is to compare 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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Type 2 Diabetes Mellitus	Drug: biphasic insulin aspart 30	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 437 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 24-week, Multinational, Multicentre, Randomised, Open Label, Parallel-group Treat-to-target Trial to Compare 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
• Actual Study Start Date: Oct 19, 2015
• Actual Primary Completion Date: Mar 18, 2017
• Actual Study Completion Date: Apr 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BIAsp 30 TID	Drug: biphasic insulin aspart 30; Administered subcutaneously (s.c., under the skin) thrice daily or twice daily. Subjects will continue with metformin all throughout the trial.
Active Comparator: BIAsp 30 BID	Drug: biphasic insulin aspart 30; Administered subcutaneously (s.c., under the skin) thrice daily or twice daily. Subjects will continue with metformin all throughout the trial.

Outcome Measures

Primary Outcome Measures

1. Change in Glycosylated Haemoglobin (HbA1c) [Week 0, Week 24]

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

Secondary Outcome Measures

1. Proportion of Subjects Achieving HbA1c Below 7.0% [Week 24]

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

2. Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes. [Week 24]

   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.

3. Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification) [Week 24]

   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.

4. Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition [Week 0-24]

   ADA classification of hypoglycaemia: 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 Asymptomatic:Episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L Documented symptomatic:Episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤3.9 mmol/L 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 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

5. Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition [Week 0-24]

   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: Severe hypoglycaemia: According to the ADA classification. 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. 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.

6. Change From Baseline in FPG by Central Laboratory Analysis [Week 0, Week 24]

   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.

7. 7-point SMPG Profile [Week 24]

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

8. 7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal) [Week 0, Week 24]

   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.

9. 7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal) [Week 0, Week 24]

   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.

10. 7-point SMPG Profiles: Change From Baseline in Mean of 2-hour PPG Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) [Week 0, Week 24]

    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.

11. 7-point SMPG Profiles: Change From Baseline in Mean of PPG Increment Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal) [Week 0, Week 24]

    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.

12. 7-point SMPG Profiles: Change From Baseline in Mean of the 7-point Profile [Week 0, Week 24]

    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.

13. 7-point SMPG Profiles: Fluctuation in the 7-point Profile [Week 24]

    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.

14. Incidence of Treatment Emergent Adverse Events (TEAEs) [Week 0-24]

    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.

15. Total Daily Insulin Dose [Week 1, Week 24]

    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.

16. Change From Baseline in Body Weight [Week 0, Week 24]

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

17. Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs) [Week 0, Week 24]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female, age at least 18 years at the time of signing informed consent. For Algeria only: age at least 19 years at the time of signing informed consent

• Type 2 diabetes subjects clinically diagnosed for at least 12 months prior to the day of screening (Visit 1)

• Treated with basal insulin for at least 90 days prior to the day of screening (Visit 1). The following basal insulin are allowed : insulin analogue once daily (OD) Neutral Protamine Hagedorn (NPH) OD or BID (twice daily)

• Treatment with metformin with or without one additional OAD (oral antidiabetic drug) for at least 90 days prior to the day of screening (Visit 1) Metformin must be at a stable dose of at least 1500 mg daily or maximum tolerated dose for at least 60 days prior to screening (Visit 1) One additional OAD:Sulphonylurea/Glinides/ a-glucosidase inhibitors/Dipeptidyl-peptidase-4 inhibitors/Sodium glucose co-transporter 2 (SGLT2) inhibitors (if applicable)

• HbA1c (glycosylated haemoglobin) 7.5%-10.0% (both inclusive) by central laboratory analysis at screening (Visit 1)

• Able and willing to intake three main meals daily (breakfast, lunch and main evening meal) throughout the trial. Definition of main meal as judged by the investigator

Exclusion Criteria:

• Previous insulin intensification regimen for more than 14 days: premixed insulin thrice daily, basal-bolus regimen or continuous subcutaneous insulin infusion (CSII). Treatment during hospitalisation or during gestational diabetes is allowed for periods longer than 14 days

• Anticipated initiation or change in concomitant medications for more than 14 consecutive days or on a frequent basis known to affect weight or glucose metabolism (e.g. orlistat, thyroid hormones, systemic corticosteroids)

• Impaired liver function, defined as alanine aminotransferase (ALT) equal to or above 2.5 times upper normal limit at screening (Visit 1)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Algiers		Algeria	16000
2	Novo Nordisk Investigational Site	Algiers		Algeria	16049
3	Novo Nordisk Investigational Site	Oran		Algeria	31000
4	Novo Nordisk Investigational Site	Hefei	Anhui	China	230001
5	Novo Nordisk Investigational Site	Beijing	Beijing	China	100029
6	Novo Nordisk Investigational Site	Beijing	Beijing	China	100071
7	Novo Nordisk Investigational Site	Beijing	Beijing	China	100144
8	Novo Nordisk Investigational Site	Beijing	Beijing	China	100191
9	Novo Nordisk Investigational Site	Beijing	Beijing	China	100730
10	Novo Nordisk Investigational Site	ChongQing	Chongqing	China	404000
11	Novo Nordisk Investigational Site	Fuzhou	Fujian	China	350001
12	Novo Nordisk Investigational Site	Guangzhou	Guangdong	China	510515
13	Novo Nordisk Investigational Site	Shenzhen	Guangdong	China	518035
14	Novo Nordisk Investigational Site	Shijiazhuang	Hebei	China	050000
15	Novo Nordisk Investigational Site	Changzhou	Jiangsu	China	213003
16	Novo Nordisk Investigational Site	Nanjing	Jiangsu	China	210011
17	Novo Nordisk Investigational Site	Nanjing	Jiangsu	China	210012
18	Novo Nordisk Investigational Site	Nanjing	Jiangsu	China	210029
19	Novo Nordisk Investigational Site	Suzhou	Jiangsu	China	215006
20	Novo Nordisk Investigational Site	Wuxi	Jiangsu	China	214023
21	Novo Nordisk Investigational Site	Zhenjiang	Jiangsu	China	212001
22	Novo Nordisk Investigational Site	Nanchang	Jiangxi	China	330006
23	Novo Nordisk Investigational Site	Changchun	Jilin	China	130021
24	Novo Nordisk Investigational Site	Dalian	Liaoning	China	116011
25	Novo Nordisk Investigational Site	Shanghai	Shanghai	China	200072
26	Novo Nordisk Investigational Site	Shanghai	Shanghai	China	200240
27	Novo Nordisk Investigational Site	Chengdu	Sichuan	China	610071
28	Novo Nordisk Investigational Site	Tianjin	Tianjin	China	300052
29	Novo Nordisk Investigational Site	Shatin, New Territories		Hong Kong
30	Novo Nordisk Investigational Site	Visakhapatnam	Andhra Pradesh	India	530002
31	Novo Nordisk Investigational Site	Guwahati	Assam	India	781006
32	Novo Nordisk Investigational Site	Bangalore	Karnataka	India	560002
33	Novo Nordisk Investigational Site	Bangalore	Karnataka	India	560038
34	Novo Nordisk Investigational Site	Mysore	Karnataka	India	570001
35	Novo Nordisk Investigational Site	Madurai	Tamil Nadu	India	625 020
36	Novo Nordisk Investigational Site	Kolkata	West Bengal	India	700080
37	Novo Nordisk Investigational Site	New Delhi		India	110088
38	Novo Nordisk Investigational Site	Kaohsiung		Taiwan	813
39	Novo Nordisk Investigational Site	Taichung City		Taiwan	407
40	Novo Nordisk Investigational Site	Taipei		Taiwan	11217
41	Novo Nordisk Investigational Site	Taipei		Taiwan	114
42	Novo Nordisk Investigational Site	Adana		Turkey	01130
43	Novo Nordisk Investigational Site	Bursa		Turkey	16059
44	Novo Nordisk Investigational Site	Istanbul		Turkey	34093
45	Novo Nordisk Investigational Site	Istanbul		Turkey	34390
46	Novo Nordisk Investigational Site	Kahramanmaras		Turkey	46000
47	Novo Nordisk Investigational Site	Dnipro		Ukraine	49005
48	Novo Nordisk Investigational Site	Kiev		Ukraine	01004
49	Novo Nordisk Investigational Site	Lviv		Ukraine	79010
50	Novo Nordisk Investigational Site	Ternopil		Ukraine	46002

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 13, 2017

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

None provided.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT02582242
• Other Study ID Numbers: BIASP-4200; U1111-1162-5508
• First Posted: Oct 21, 2015
• Last Update Posted: Jun 11, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Aspart; Biphasic Insulins; Insulin aspart, insulin aspart protamine drug combination 30:70

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	220	217
COMPLETED	200	200
NOT COMPLETED	20	17

Baseline Characteristics

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	220	217	437
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.0 (9.8)	56.6 (9.3)	56.8 (9.5)
Sex: Female, Male (Count of Participants)
Female	112 50.9%	108 49.8%	220 50.3%
Male	108 49.1%	109 50.2%	217 49.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 0.9%	0 0%	2 0.5%
Not Hispanic or Latino	218 99.1%	217 100%	435 99.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	181 82.3%	170 78.3%	351 80.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	39 17.7%	47 21.7%	86 19.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Glycosylated haemoglobin (HbA1c) (Percentage of HbA1c) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of HbA1c]	8.74 (0.69)	8.68 (0.69)	8.71 (0.69)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	8.68 (2.68)	8.72 (2.39)	8.70 (2.54)
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	71.57 (13.38)	72.24 (13.01)	71.90 (13.19)

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c)
Description	Change from baseline in HbA1c was evaluated after 24 weeks of treatment. Missing data was imputed using the last observation carried forward (LOCF) method.
Time Frame	Week 0, Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Mean (Standard Deviation) [Percentage (%) of HbA1c]	-1.66 (1.00)	-1.52 (0.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Biphasic Insulin Aspart 30 (Three Times Daily), Biphasic Insulin Aspart 30 (Twice Daily)
	Comments	The analysis was based on a mixed-effect model for repeated measures including changes from baseline in HbA1c at visit 6, 10, 14, 18, 22 and 26 (in week 4, 8, 12, 16, 20 and 24, respectively). The model included treatment, strata and region as fixed factors, subject as random effect, baseline HbA1c as covariate and interaction between all fixed effects and visit, and between the covariate and visit.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2601
	Comments
	Method	Mixed model for repeated measurements
	Comments
Method of Estimation	Estimation Parameter	Treatment difference at week 24
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference at week 24: BIAsp 30 (TID) - BIAsp 30 (BID). Number of subjects contributed to the statistical analysis: N=217 for BIAsp 30 (TID) and N=213 for BIAsp 30 (BID).

2. Secondary Outcome

Title	Proportion of Subjects Achieving HbA1c Below 7.0%
Description	Percentage of subjects achieving HbA1c <7.0% (yes or no) was evaluated after 24 weeks of treatment.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Yes	54.5 24.8%	47.5 21.9%
No	45.5 20.7%	52.5 24.2%

3. Secondary Outcome

Title	Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes.
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Yes	50.0 22.7%	44.7 20.6%
No	50.0 22.7%	55.3 25.5%

4. Secondary Outcome

Title	Proportion of Subjects Achieving HbA1c Below 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes (According to the Novo Nordisk Classification)
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Yes	27.3 12.4%	21.7 10%
No	72.7 33%	78.3 36.1%

5. Secondary Outcome

Title	Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) Definition
Description	ADA classification of hypoglycaemia: 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 Asymptomatic:Episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L Documented symptomatic:Episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤3.9 mmol/L 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 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
Time Frame	Week 0-24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Severe	3	3
Asymptomatic	397	344
Documented symptomatic	642	765
Pseudo-hypoglycaemia	54	93
Probable symptomatic	61	30

6. Secondary Outcome

Title	Number of Treatment Emergent Hypoglycaemic Episodes Classified According to Novo Nordisk Definition
Description	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: Severe hypoglycaemia: According to the ADA classification. 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. 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.
Time Frame	Week 0-24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Severe	3	3
BG confirmed	249	249
Severe or BG confirmed	252	252
Severe or BG confirmed symptomatic	195	223
NN unclassifiable	905	983

7. Secondary Outcome

Title	Change From Baseline in FPG by Central Laboratory Analysis
Description	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.
Time Frame	Week 0, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Mean (Standard Deviation) [mmol/L]	-1.34 (3.10)	-1.07 (2.64)

8. Secondary Outcome

Title	7-point SMPG Profile
Description	7-point self-measured plasma glucose (SMPG) profiles was evaluated after 24 weeks of treatment. Subjects were instructed to perform the following SMPG measurements: Before breakfast. 120 minutes after the start of breakfast. Before lunch. 120 minutes after the start of lunch. Before main evening meal. 120 minutes after the start of main evening meal. At bedtime. Missing data was imputed using the LOCF method.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Before breakfast	6.87 (1.61)	6.86 (1.71)
120 minutes after start of breakfast	9.33 (3.14)	9.04 (3.20)
Before lunch	6.86 (2.21)	7.09 (2.72)
120 minutes after start of lunch	9.48 (3.02)	9.92 (3.54)
Before main evening meal	7.26 (2.08)	7.68 (2.53)
120 minutes after start of main evening meal	8.77 (3.00)	9.09 (3.29)
At bedtime	7.69 (2.50)	8.24 (3.15)

9. Secondary Outcome

Title	7-point SMPG Profiles: Change From Baseline in 2-hour PPG at Individual Meal (Breakfast, Lunch and Main Evening Meal)
Description	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.
Time Frame	Week 0, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Change in PPG breakfast	-4.17 (4.84)	-4.03 (4.22)
Change in PPG lunch	-3.43 (4.56)	-3.27 (4.59)
Change in PPG main evening meal	-4.38 (4.44)	-4.09 (4.71)

10. Secondary Outcome

Title	7-point SMPG Profiles: Change From Baseline in PPG Increment at Individual Meal (Breakfast, Lunch and Main Evening Meal)
Description	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.
Time Frame	Week 0, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Change in PPG increment breakfast	-2.06 (4.44)	-2.02 (3.95)
Change in PPG increment lunch	-0.13 (4.38)	-0.14 (4.40)
Change in PPG increment main evening meal	-0.64 (4.55)	-1.60 (4.72)

11. Secondary Outcome

Title	7-point SMPG Profiles: Change From Baseline in Mean of 2-hour PPG Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal)
Description	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.
Time Frame	Week 0, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Mean (Standard Deviation) [mmol/L]	-3.98 (3.59)	-3.77 (3.48)

12. Secondary Outcome

Title	7-point SMPG Profiles: Change From Baseline in Mean of PPG Increment Over 3 Main Meals (Breakfast, Lunch and Main Evening Meal)
Description	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.
Time Frame	Week 0, Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Mean (Standard Deviation) [mmol/L]	-0.96 (2.53)	-1.22 (2.68)

13. Secondary Outcome

Title	7-point SMPG Profiles: Change From Baseline in Mean of the 7-point Profile
Description	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.
Time Frame	Week 0, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Mean (Standard Deviation) [mmol/L]	-3.58 (3.08)	-3.27 (2.84)

14. Secondary Outcome

Title	7-point SMPG Profiles: Fluctuation in the 7-point Profile
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Geometric Mean (Geometric Coefficient of Variation) [mmol/L]	1.04 (54.04)	1.05 (54.39)

15. Secondary Outcome

Title	Incidence of Treatment Emergent Adverse Events (TEAEs)
Description	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.
Time Frame	Week 0-24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Number [Number of adverse events]	275	251

16. Secondary Outcome

Title	Total Daily Insulin Dose
Description	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.
Time Frame	Week 1, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Week 1	24.5 (10.0)	24.2 (13.0)
Week 24	67.4 (35.5)	63.4 (33.1)

17. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Change from baseline in body weight was evaluated after 24 weeks of treatment. Missing data was imputed using the LOCF method.
Time Frame	Week 0, Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Mean (Standard Deviation) [Kilogram (kg)]	1.45 (3.11)	1.65 (2.85)

18. Secondary Outcome

Title	Change From Baseline in Patient-reported Treatment Satisfaction as Assessed by the Diabetes Treatment Satisfaction Questionnaire (Status) (DTSQs)
Description	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.
Time Frame	Week 0, Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)	Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.	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.
Measure Participants	220	217
Overall treatment satisfaction	2	4
Hypoglycaemia	0	0
Hyperglycaemia	-1	-1

Adverse Events

Time Frame	Week 0 to week 24 + 7 days. All AEs are treatment emergent, i.e., TEAEs.
Adverse Event Reporting Description	Results are based on the safety analysis set, which included all subjects who received at least one dose of investigational product (BIAsp 30).
Arm/Group Title	Biphasic Insulin Aspart 30 (Three Times Daily)		Biphasic Insulin Aspart 30 (Twice Daily)
Arm/Group Description	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.		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.
All Cause Mortality
	Biphasic Insulin Aspart 30 (Three Times Daily)		Biphasic Insulin Aspart 30 (Twice Daily)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/220 (0%)		0/217 (0%)
Serious Adverse Events
	Biphasic Insulin Aspart 30 (Three Times Daily)		Biphasic Insulin Aspart 30 (Twice Daily)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/220 (5.5%)		9/217 (4.1%)
Blood and lymphatic system disorders
Anaemia	1/220 (0.5%)	1	0/217 (0%)	0
Cardiac disorders
Acute coronary syndrome	1/220 (0.5%)	1	0/217 (0%)	0
Angina unstable	1/220 (0.5%)	1	0/217 (0%)	0
Coronary artery disease	0/220 (0%)	0	2/217 (0.9%)	2
Mitral valve incompetence	1/220 (0.5%)	1	0/217 (0%)	0
Eye disorders
Diabetic retinopathy	0/220 (0%)	0	1/217 (0.5%)	1
Vitreous haemorrhage	0/220 (0%)	0	1/217 (0.5%)	1
Gastrointestinal disorders
Intestinal polyp	1/220 (0.5%)	1	0/217 (0%)	0
General disorders
Oedema	0/220 (0%)	0	1/217 (0.5%)	1
Infections and infestations
Pneumonia	1/220 (0.5%)	1	0/217 (0%)	0
Wound infection	1/220 (0.5%)	1	0/217 (0%)	0
Injury, poisoning and procedural complications
Craniocerebral injury	1/220 (0.5%)	1	0/217 (0%)	0
Laceration	1/220 (0.5%)	1	0/217 (0%)	0
Rib fracture	0/220 (0%)	0	1/217 (0.5%)	1
Road traffic accident	0/220 (0%)	0	1/217 (0.5%)	1
Soft tissue injury	1/220 (0.5%)	1	0/217 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/220 (0%)	0	1/217 (0.5%)	1
Musculoskeletal and connective tissue disorders
Trigger finger	0/220 (0%)	0	1/217 (0.5%)	1
Nervous system disorders
Cerebral infarction	0/220 (0%)	0	1/217 (0.5%)	1
Diabetic neuropathy	2/220 (0.9%)	2	0/217 (0%)	0
Hypoglycaemic seizure	0/220 (0%)	0	1/217 (0.5%)	1
Lacunar infarction	0/220 (0%)	0	1/217 (0.5%)	1
Renal and urinary disorders
Diabetic nephropathy	1/220 (0.5%)	1	0/217 (0%)	0
Skin and subcutaneous tissue disorders
Diabetic foot	0/220 (0%)	0	1/217 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Biphasic Insulin Aspart 30 (Three Times Daily)		Biphasic Insulin Aspart 30 (Twice Daily)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/220 (15.5%)		36/217 (16.6%)
Infections and infestations
Upper respiratory tract infection	26/220 (11.8%)	31	27/217 (12.4%)	32
Nervous system disorders
Headache	10/220 (4.5%)	16	11/217 (5.1%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.