Trial Outcomes & Findings for Treatment Intensification With Biphasic Insulin Aspart 30 in Subjects With Type 2 Diabetes Inadequately Controlled on Sitagliptin and Metformin (NCT NCT01519674)

Results Overview

Estimated mean change from baseline in HbA1c after 24 weeks of treatment.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

582 participants

Primary outcome timeframe

Week 0 to Week 24

Results posted on

2017-02-24

Participant Flow

The trial was conducted at 60 sites in 10 countries as follows: Argentina (6); Australia (2); Brazil (4); Greece (5); India (17); Malaysia (3); Portugal (6); Republic of Korea (7); Thailand (5); Turkey (5)

Subjects on pre-trial metformin (1000 mg/day) (± additional OAD treatment) continued their medication. Subjects on pre-trial sitagliptin (100 mg/day) either continued or discontinued their sitagliptin treatment depending on the treatment group the subjects were randomised to.

Participant milestones

Participant milestones
Measure	BID + Met Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Overall Study STARTED	194	195	193
Overall Study Exposed	192	193	190
Overall Study COMPLETED	173	182	181
Overall Study NOT COMPLETED	21	13	12

Reasons for withdrawal

Reasons for withdrawal
Measure	BID + Met Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Overall Study Adverse Event	3	3	0
Overall Study Lack of Efficacy	1	1	1
Overall Study Protocol Violation	0	3	1
Overall Study Withdrawal Criteria	7	2	7
Overall Study Unsclassified	10	4	3

Baseline Characteristics

Treatment Intensification With Biphasic Insulin Aspart 30 in Subjects With Type 2 Diabetes Inadequately Controlled on Sitagliptin and Metformin

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BID + Met n=194 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=195 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=193 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	Total n=582 Participants Total of all reporting groups
Age, Continuous	54.8 years STANDARD_DEVIATION 9.5 • n=5 Participants	56.3 years STANDARD_DEVIATION 10.2 • n=7 Participants	55.7 years STANDARD_DEVIATION 10.4 • n=5 Participants	55.6 years STANDARD_DEVIATION 10.0 • n=4 Participants
Gender Female	83 Participants n=5 Participants	101 Participants n=7 Participants	97 Participants n=5 Participants	281 Participants n=4 Participants
Gender Male	111 Participants n=5 Participants	94 Participants n=7 Participants	96 Participants n=5 Participants	301 Participants n=4 Participants
Body Weight	79.4 kg STANDARD_DEVIATION 15.8 • n=5 Participants	78.3 kg STANDARD_DEVIATION 16.1 • n=7 Participants	77.5 kg STANDARD_DEVIATION 16.8 • n=5 Participants	78.4 kg STANDARD_DEVIATION 16.2 • n=4 Participants
Body Mass Index (BMI)	29.3 kg/m^2 STANDARD_DEVIATION 4.3 • n=5 Participants	29.4 kg/m^2 STANDARD_DEVIATION 4.5 • n=7 Participants	29.4 kg/m^2 STANDARD_DEVIATION 5.0 • n=5 Participants	29.4 kg/m^2 STANDARD_DEVIATION 4.6 • n=4 Participants
Glycosylated haemoglobin (HbA1c)	8.4 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=5 Participants	8.4 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=7 Participants	8.4 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=5 Participants	8.4 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=4 Participants
Fasting plasma glucose (FPG)	8.9 mmol/L STANDARD_DEVIATION 2.2 • n=5 Participants	9.3 mmol/L STANDARD_DEVIATION 2.8 • n=7 Participants	8.7 mmol/L STANDARD_DEVIATION 2.7 • n=5 Participants	9.0 mmol/L STANDARD_DEVIATION 2.6 • n=4 Participants

PRIMARY outcome

Timeframe: Week 0 to Week 24

Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 559 subjects contributed to the statistical analysis at Week 24.

Estimated mean change from baseline in HbA1c after 24 weeks of treatment.

Outcome measures

Outcome measures
Measure	BID + Met n=183 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=189 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=187 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Change From Baseline in HbA1c (Glycosylated Haemoglobin)	-1.27 percentage of glycosylated haemoglobin Standard Error 0.07	-1.51 percentage of glycosylated haemoglobin Standard Error 0.07	-1.15 percentage of glycosylated haemoglobin Standard Error 0.07

SECONDARY outcome

Timeframe: After 24 weeks of treatment

Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 559 subjects contributed to the statistical analysis at Week 24.

Proportion of subjects achieving HbA1c below 7.0% after 24 weeks of treatment

Outcome measures

Outcome measures
Measure	BID + Met n=183 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=189 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=187 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Responder for HbA1c, Proportion of Subjects Achieving Pre-defined HbA1c Targets (HbA1c < 7.0%)	49.7 percentage (%) of subjects	59.8 percentage (%) of subjects	46.5 percentage (%) of subjects

SECONDARY outcome

Timeframe: After 24 weeks of treatment

Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 559 subjects contributed to the statistical analysis at Week 24.

Proportion of subjects achieving HbA1c equal to or below 6.5% after 24 weeks of treatment.

Outcome measures

Outcome measures
Measure	BID + Met n=183 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=189 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=187 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Responder for HbA1c, Proportion of Subjects Achieving Pre-defined HbA1c Targets (HbA1c ≤ 6.5%)	30.6 percentage (%) of subjects	40.7 percentage (%) of subjects	25.1 percentage (%) of subjects

SECONDARY outcome

Timeframe: Week 0 to Week 24

Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 556 subjects contributed to the statistical analysis at Week 24.

Estimated mean change from baseline in fasting plasma glucose (FPG)

Outcome measures

Outcome measures
Measure	BID + Met n=181 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=188 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=187 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Change From Baseline in Fasting Plasma Glucose (FPG)	-1.90 mmol/L Standard Error 0.14	-2.03 mmol/L Standard Error 0.14	-1.96 mmol/L Standard Error 0.14

SECONDARY outcome

Timeframe: After 24 weeks of treatment

Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 555 subjects contributed to the statistical analysis at Week 24.

Estimated mean post prandial increments at breakfast after 24 weeks of treatment.

Outcome measures

Outcome measures
Measure	BID + Met n=184 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=187 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=184 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Prandial Plasma Glucose (PPG) Increments at Breakfast	2.01 mmol/L Standard Error 0.19	1.73 mmol/L Standard Error 0.19	2.89 mmol/L Standard Error 0.19

SECONDARY outcome

Timeframe: After 24 weeks of treatment

Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 548 subjects contributed to the statistical analysis at Week 24.

Estimated mean post prandial increments at lunch after 24 weeks of treatment.

Outcome measures

Outcome measures
Measure	BID + Met n=180 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=186 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=182 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Prandial Plasma Glucose (PPG) Increments at Lunch.	3.05 mmol/L Standard Error 0.22	2.19 mmol/L Standard Error 0.21	2.52 mmol/L Standard Error 0.21

SECONDARY outcome

Timeframe: After 24 weeks of treatment

Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 550 subjects contributed to the statistical analysis at Week 24.

Estimated mean post prandial increments at dinner after 24 weeks of treatment.

Outcome measures

Outcome measures
Measure	BID + Met n=178 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=188 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=184 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Prandial Plasma Glucose (PPG) Increments at Dinner.	0.89 mmol/L Standard Error 0.21	1.01 mmol/L Standard Error 0.20	0.17 mmol/L Standard Error 0.21

SECONDARY outcome

Timeframe: After 24 weeks of treatment

Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 557 subjects contributed to the statistical analysis at Week 24.

Estimated overall mean post prandial increment after 24 weeks of treatment.

Outcome measures

Outcome measures
Measure	BID + Met n=184 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=188 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=185 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Prandial Plasma Glucose (PPG) Overall Mean Increment.	1.97 mmol/L Standard Error 0.12	1.66 mmol/L Standard Error 0.12	1.88 mmol/L Standard Error 0.12

SECONDARY outcome

Timeframe: Week 0 to Week 24

Population: Safety analysis set included all subjects receiving at least one dose of the investigational product.

Rate of AEs per 100 years of patient exposure. An adverse event was defined as treatment emergent if the event had onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment.

Outcome measures

Outcome measures
Measure	BID + Met n=192 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=193 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=190 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Adverse Events (AEs) Serious adverse events	8.4 Events/100 years of patient exposure	5.8 Events/100 years of patient exposure	10.5 Events/100 years of patient exposure
Adverse Events (AEs) Severe adverse events	6.0 Events/100 years of patient exposure	10.5 Events/100 years of patient exposure	7.0 Events/100 years of patient exposure
Adverse Events (AEs) Moderate adverse events	71.0 Events/100 years of patient exposure	74.6 Events/100 years of patient exposure	79.7 Events/100 years of patient exposure
Adverse Events (AEs) All treatment emergent adverse events	262.2 Events/100 years of patient exposure	209.9 Events/100 years of patient exposure	281.2 Events/100 years of patient exposure
Adverse Events (AEs) Mild adverse events	185.2 Events/100 years of patient exposure	124.8 Events/100 years of patient exposure	194.5 Events/100 years of patient exposure
Adverse Events (AEs) Fatal adverse events	0 Events/100 years of patient exposure	0 Events/100 years of patient exposure	0 Events/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 0 to Week 24

Population: Safety analysis set included all subjects receiving at least one dose of the investigational product.

Number of treatment emergent hypoglycaemic episodes. Treatment emergent hypoglycaemic episode: if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Nocturnal: Time of onset between 00:01 and 05:59 a.m. (both included). Additional minor hypoglycaemic episode: symptomatic or asymptomatic hypoglycaemia with blood glucose (BG) values \< 2.8 mmol/L (50 mg/dL) or plasma glucose (PG) \< 3.1 mmol/L (56 mg/dL), and which was handled by the subject him/herself.

Outcome measures

Outcome measures
Measure	BID + Met n=192 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=193 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=190 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Number of Treatment Emergent Hypoglycaemic Episodes (Nocturnal and Day-time) Classified Both According to the American Diabetes Association (ADA) Definition and to an Additional Definition for Minor Episodes. Diurnal (ADA)	515 episodes	440 episodes	249 episodes
Number of Treatment Emergent Hypoglycaemic Episodes (Nocturnal and Day-time) Classified Both According to the American Diabetes Association (ADA) Definition and to an Additional Definition for Minor Episodes. Nocturnal (ADA)	68 episodes	54 episodes	63 episodes
Number of Treatment Emergent Hypoglycaemic Episodes (Nocturnal and Day-time) Classified Both According to the American Diabetes Association (ADA) Definition and to an Additional Definition for Minor Episodes. Diurnal (additional minor)	163 episodes	112 episodes	71 episodes
Number of Treatment Emergent Hypoglycaemic Episodes (Nocturnal and Day-time) Classified Both According to the American Diabetes Association (ADA) Definition and to an Additional Definition for Minor Episodes. Nocturnal (additional minor)	21 episodes	14 episodes	23 episodes

SECONDARY outcome

Timeframe: Week 0 to Week 24

Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 545 subjects contributed to the statistical analysis at Week 24.

Estimated mean change from baseline in Treatment Related Impact Measure - Diabetes (TRIM-D) 'total score' to end of trial. The score measured treatment satisfaction. The scores were transformed to a 0-100 scale with higher scores indicating greater satisfaction.

Outcome measures

Outcome measures
Measure	BID + Met n=178 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=184 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=183 Participants Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Change From Baseline in Patient Reported Outcome by Use of the Treatment Related Impact Measure - Diabetes.	6.22 scores Standard Error 0.82	5.93 scores Standard Error 0.81	6.20 scores Standard Error 0.81

Adverse Events

BID + Met

Serious events: 7 serious events

Other events: 30 other events

Deaths: 0 deaths

BID + Sita + Met

Serious events: 5 serious events

Other events: 25 other events

Deaths: 0 deaths

OD + Sita + Met

Serious events: 4 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	BID + Met n=192 participants at risk Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=193 participants at risk Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=190 participants at risk Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Gastrointestinal disorders Diarrhoea	4.2% 8/192 • Number of events 10 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.52% 1/193 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	5.3% 10/190 • Number of events 10 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Infections and infestations Influenza	5.7% 11/192 • Number of events 14 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	2.6% 5/193 • Number of events 6 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	5.3% 10/190 • Number of events 12 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Infections and infestations Nasopharyngitis	4.7% 9/192 • Number of events 9 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	5.7% 11/193 • Number of events 12 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	4.2% 8/190 • Number of events 9 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Nervous system disorders Headache	3.6% 7/192 • Number of events 11 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	5.7% 11/193 • Number of events 19 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	4.2% 8/190 • Number of events 15 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.

Additional Information

Public Access to Clinical Trials

Novo Nordisk A/S

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Novo Nordisk maintains the right to be informed of any Investigator plans for publication and to review any scientific paper, presentation, communication or other information concerning the investigation described in this protocol. Novo Nordisk reserves the right to prior review of such publications and to ask for delay of publication of individual site results until after the primary manuscript is accepted for publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	BID + Met n=192 participants at risk Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.	BID + Sita + Met n=193 participants at risk Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.	OD + Sita + Met n=190 participants at risk Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
Blood and lymphatic system disorders Anaemia	0.52% 1/192 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Cardiac disorders Supraventricular tachycardia	0.52% 1/192 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
General disorders Pyrexia	0.00% 0/192 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.53% 1/190 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Immune system disorders Drug hypersensitivity	0.52% 1/192 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Infections and infestations Gastroenteritis	0.00% 0/192 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.53% 1/190 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Infections and infestations Liver abscess	0.52% 1/192 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Injury, poisoning and procedural complications Burns second degree	0.52% 1/192 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/192 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.52% 1/193 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Metabolism and nutrition disorders Hypoglycaemia	0.52% 1/192 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.52% 1/193 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.53% 1/190 • Number of events 4 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/192 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.52% 1/193 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/192 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.53% 1/190 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.00% 0/192 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.52% 1/193 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid cancer metastatic	0.52% 1/192 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Nervous system disorders Haemorrhagic stroke	0.00% 0/192 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.53% 1/190 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Nervous system disorders Hypoglycaemic unconsciousness	0.00% 0/192 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/193 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.53% 1/190 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.
Nervous system disorders VIIth nerve paralysis	0.00% 0/192 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.52% 1/193 • Number of events 1 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.	0.00% 0/190 • Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Safety analysis set included all subjects receiving at least one dose of the investigational product.