Comparison of Two NN5401 Formulations Versus Insulin Glargine, All in Combination With Metformin in Subjects With Type 2 Diabetes

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00614055
• Collaborator: (none)
• Enrollment: 178
• Locations: 28
• Arms: 3
• Duration (Months): 6
• Patients Per Site: 6.4
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This trial is conducted in Europe. The aim of this trial is to compare two NN5401 (SIAC, insulin degludec/insulin aspart) formulations with each other and with insulin glargine, all in combination with metformin in insulin naive subjects with type 2 diabetes.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: insulin degludec/insulin aspart; Drug: insulin degludec/insulin aspart; Drug: insulin glargine; Drug: metformin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 178 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 16 Week Randomised, Open Labelled, 3 Armed, Parallel Group, Treat-to-target Trial Comparing Once Daily Injection of SIAC 30 (B), SIAC 45 (B) and Insulin Glargine, All in Combination With Metformin in Subjects With Type 2 Diabetes Failing on OAD Treatment
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Insulin glargine	Drug: insulin glargine; Treat-to-target dose titration scheme, injection s.c., once daily; Drug: metformin; Tablets, 1500-2000 mg/day
Experimental: SIAC 30 (B)	Drug: insulin degludec/insulin aspart; Formulation 1: Treat-to-target dose titration scheme, injection s.c., once daily; Drug: metformin; Tablets, 1500-2000 mg/day
Experimental: SIAC 45 (B)	Drug: insulin degludec/insulin aspart; Formulation 2: Treat-to-target dose titration scheme, injection s.c., once daily; Drug: metformin; Tablets, 1500-2000 mg/day

Outcome Measures

Primary Outcome Measures

1. Change in Glycosylated Haemoglobin (HbA1c) [Week 0, Week 16]

   Change from baseline in HbA1c after 16 weeks of treatment

Secondary Outcome Measures

1. Change in Fasting Plasma Glucose (FPG) [Week 0, Week 16]

   Change from baseline in FPG after 16 weeks of treatment

2. Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) [Week 16]

   Mean of SMPG after 16 weeks of treatment. Plasma glucose measured: before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner, bedtime, at 4 am and before breakfast.

3. Rate of Treatment Emergent Adverse Events (AEs) [Week 0 to Week 16 + 5 days follow up]

   Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect.

4. Rate of Major and Minor Hypoglycaemic Episodes [Week 0 to Week 16 + 5 days follow up]

   Rate of Major and Minor hypoglycaemic episodes per 100 patient years of exposure (PYE). Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L.

5. Rate of Nocturnal Major and Minor Hypoglycaemic Episodes [Week 0 to Week 16 + 5 days follow up]

   Rate of nocturnal Major and Minor hypoglycaemic episodes per 100 patient years of exposure (PYE). Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L. Episodes were defined as nocturnal if the time of onset was between 23:00 (included) and 06:00 (excluded).

6. Laboratory Safety Parameters (Biochemistry): Alanine Aminotransferase (ALAT) [Week -4, Week 16]

   Values at screening (Week -4) and at Week 16

7. Laboratory Safety Parameters (Biochemistry): Aspartate Aminotransferase (ASAT) [Week -4, Week 16]

   Values at screening (Week -4) and at Week 16

8. Laboratory Safety Parameters (Biochemistry): Serum Creatinine [Week -4, Week 16]

   Values at screening (Week -4) and at Week 16

9. Vital Signs: Diastolic Blood Pressure (BP) [Week 0, Week 16]

   Values at baseline (Week 0) and at Week 16

10. Vital Signs: Systolic Blood Pressure (BP) [Week 0, Week 16]

    Values at baseline (Week 0) and at Week 16

11. Vital Signs: Pulse [Week 0, Week 16]

    Values at baseline (Week 0) and at Week 16

12. Physical Examination [Week 0, Week 8, Week 16]

    Physical examination is performed at baseline (Week 0) and after 8 and 16 weeks of treatment. If any new findings or deterioration in previous findings were observed during the trial, these were recorded as AEs and are therefore not presented separately as no analysis was performed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject.)

• Insulin naïve type 2 diabetes subjects (as diagnosed clinically) for at least 3 months (no previous insulin treatment or previous short term insulin treatment maximum 14 days within the last 3 months)

• Treatment with one or two oral anti-diabetic drugs (OADs): metformin, sulfonylurea, other insulin secretagogue (e.g. repaglinide, nateglinide), alpha-glucosidase inhibitors for at least 2 month at a stable maximum tolerated dose or at least half maximum allowed dose according to locally approved summary of product characteristics (SPC)

• HbA1c, 7.0 - 11.0 % (both inclusive)

• Body Mass Index (BMI), 25.0 - 37.0 kg/m^2 (both inclusive)

Exclusion Criteria:

• Metformin contraindication according to local practice

• Thiazolidinedione (TZD) treatments within the previous three months prior to Visit 1

• Any systemic treatment with products, which in the investigator's opinion could interfere with glucose or lipid metabolism (e.g. systemic corticosteroids) within 3 months prior to randomisation

• Subject has a clinically significant, active (during the past 12 months) disease of the gastrointestinal, pulmonary, neurological, genitourinary, or haematological system that, in the opinion of the investigator, may confound the results of the trial or pose additional risk in administering trial product

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Alès		France	30100
2	Novo Nordisk Investigational Site	Brest		France	29609
3	Novo Nordisk Investigational Site	LA ROCHELLE cedex		France	17019
4	Novo Nordisk Investigational Site	Le Creusot		France	71200
5	Novo Nordisk Investigational Site	Mont de Marsan		France	40024
6	Novo Nordisk Investigational Site	Venissieux		France	69200
7	Novo Nordisk Investigational Site	Bad Kreuznach		Germany	55545
8	Novo Nordisk Investigational Site	Bad Mergentheim		Germany	97980
9	Novo Nordisk Investigational Site	Dormagen		Germany	41539
10	Novo Nordisk Investigational Site	Hohenmölsen		Germany	06679
11	Novo Nordisk Investigational Site	Neuss		Germany	41460
12	Novo Nordisk Investigational Site	Neuwied		Germany	56564
13	Novo Nordisk Investigational Site	Elverum		Norway	2408
14	Novo Nordisk Investigational Site	Hamar		Norway	2317
15	Novo Nordisk Investigational Site	Kongsvinger		Norway	2212
16	Novo Nordisk Investigational Site	Oslo		Norway	0586
17	Novo Nordisk Investigational Site	Stavanger		Norway	4011
18	Novo Nordisk Investigational Site	Tromsø		Norway	9038
19	Novo Nordisk Investigational Site	Bucharest		Romania	011234
20	Novo Nordisk Investigational Site	Bucharest		Romania	020042
21	Novo Nordisk Investigational Site	Bucharest		Romania	020475
22	Novo Nordisk Investigational Site	Bucharest		Romania	020992
23	Novo Nordisk Investigational Site	Bucharest		Romania
24	Novo Nordisk Investigational Site	Almería		Spain	04001
25	Novo Nordisk Investigational Site	Partida de Bacarot		Spain	03114
26	Novo Nordisk Investigational Site	Sevilla		Spain	41010
27	Novo Nordisk Investigational Site	Valencia		Spain	46014
28	Novo Nordisk Investigational Site	Valladolid		Spain	47011

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

None provided.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT00614055
• Other Study ID Numbers: NN5401-1791; 2007-002476-33
• First Posted: Feb 13, 2008
• Last Update Posted: Mar 20, 2017
• Last Verified: Feb 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Metformin; Insulin Glargine; Insulin Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 22 sites in 5 countries: France (4 sites), Germany (5 sites), Norway (5 sites), Romania (3 sites) and Spain (5 sites).
Pre-assignment Detail	During a run-in period of 2 weeks, metformin was up-titrated to 1500/ 2000 mg/day, which was maintained for 1 week. Subjects who tolerated the metformin dose for a week and had a median of 3 self measured glucose values before breakfast, on 3 consecutive days before randomisation, of ≥ 7.5 mmol/l, were randomised to 1 of the 3 treatment groups

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Period Title: Overall Study
STARTED	59	59	60
Exposed	59	59	60
COMPLETED	55	53	55
NOT COMPLETED	4	6	5

Baseline Characteristics

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine	Total
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Total of all reporting groups
Overall Participants	59	59	60	178
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.7 (8.8)	60.2 (8.4)	58.4 (8.4)	59.1 (8.5)
Sex: Female, Male (Count of Participants)
Female	22 37.3%	25 42.4%	16 26.7%	63 35.4%
Male	37 62.7%	34 57.6%	44 73.3%	115 64.6%
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.3 (1.2)	8.6 (1.5)	8.4 (1.3)	8.5 (1.3)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	11.1 (3.3)	11.5 (3.2)	12.1 (3.5)	11.6 (3.3)

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c)
Description	Change from baseline in HbA1c after 16 weeks of treatment
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data was imputed using last observation carried forward (LOCF).

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	-1.31 (1.01)	-1.46 (1.39)	-1.29 (1.10)

2. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG)
Description	Change from baseline in FPG after 16 weeks of treatment
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects and missing data was imputed using LOCF.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Mean (Standard Deviation) [mmol/L]	-4.30 (3.45)	-4.10 (3.09)	-5.07 (3.85)

3. Secondary Outcome

Title	Mean of 9-point Self Measured Plasma Glucose Profile (SMPG)
Description	Mean of SMPG after 16 weeks of treatment. Plasma glucose measured: before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner, bedtime, at 4 am and before breakfast.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects and missing data was imputed using LOCF.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Mean (Standard Error) [mmol/L]	8.34 (0.75)	8.31 (0.78)	8.42 (0.78)

4. Secondary Outcome

Title	Rate of Treatment Emergent Adverse Events (AEs)
Description	Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect.
Time Frame	Week 0 to Week 16 + 5 days follow up

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAS) included all subjects who received at least one dose of the investigational product or its comparator.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Adverse events (AEs)	441	310	295
Serious AEs	11	6	0
Severe AEs	6	0	0
Moderate AEs	138	123	61
Mild AEs	298	187	234
Fatal AEs	0	0	0

5. Secondary Outcome

Title	Rate of Major and Minor Hypoglycaemic Episodes
Description	Rate of Major and Minor hypoglycaemic episodes per 100 patient years of exposure (PYE). Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L.
Time Frame	Week 0 to Week 16 + 5 days follow up

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Major	0	0	0
Minor	115	240	67

6. Secondary Outcome

Title	Rate of Nocturnal Major and Minor Hypoglycaemic Episodes
Description	Rate of nocturnal Major and Minor hypoglycaemic episodes per 100 patient years of exposure (PYE). Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L. Episodes were defined as nocturnal if the time of onset was between 23:00 (included) and 06:00 (excluded).
Time Frame	Week 0 to Week 16 + 5 days follow up

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Major	0	0	0
Minor	6	158	17

7. Secondary Outcome

Title	Laboratory Safety Parameters (Biochemistry): Alanine Aminotransferase (ALAT)
Description	Values at screening (Week -4) and at Week 16
Time Frame	Week -4, Week 16

Outcome Measure Data

Analysis Population Description

The SAS included all subjects who received at least one dose of the investigational product or its comparator.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Week -4 , N=58, 59, 60	31.9 (18.3)	29.7 (15.3)	33.7 (23.1)
Week 16 , N=54, 54, 57	23.9 (13.1)	23.2 (9.7)	22.3 (10.3)

8. Secondary Outcome

Title	Laboratory Safety Parameters (Biochemistry): Aspartate Aminotransferase (ASAT)
Description	Values at screening (Week -4) and at Week 16
Time Frame	Week -4, Week 16

Outcome Measure Data

Analysis Population Description

The SAS included all subjects who received at least one dose of the investigational product or its comparator.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Week -4, N=58, 59, 60	24.8 (14.6)	22.0 (8.3)	24.0 (14.1)
Week 16, N=54, 54, 57	21.1 (8.2)	20.0 (5.8)	19.2 (6.4)

9. Secondary Outcome

Title	Laboratory Safety Parameters (Biochemistry): Serum Creatinine
Description	Values at screening (Week -4) and at Week 16
Time Frame	Week -4, Week 16

Outcome Measure Data

Analysis Population Description

The SAS included all subjects who received at least one dose of the investigational product or its comparator.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Week -4 , N=58, 59, 60	76.4 (15.4)	75.8 (14.4)	77.4 (13.9)
Week 16 , N=54, 54, 57	75.7 (15.4)	74.9 (15.6)	76.8 (14.6)

10. Secondary Outcome

Title	Vital Signs: Diastolic Blood Pressure (BP)
Description	Values at baseline (Week 0) and at Week 16
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

The SAS included all subjects who received at least one dose of the investigational product or its comparator.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Week 0 (Baseline), N=59, 59, 60	78 (8)	78 (8)	79 (8)
Week 16, N=56, 53, 58	76 (8)	77 (9)	77 (7)

11. Secondary Outcome

Title	Vital Signs: Systolic Blood Pressure (BP)
Description	Values at baseline (Week 0) and at Week 16
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

The SAS included all subjects who received at least one dose of the investigational product or its comparator.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Week 0 (Baseline), N=59, 59, 60	135 (15)	133 (14)	135 (15)
Week 16, N=56, 53, 58	129 (13)	133 (12)	129 (12)

12. Secondary Outcome

Title	Vital Signs: Pulse
Description	Values at baseline (Week 0) and at Week 16
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

The SAS included all subjects who received at least one dose of the investigational product or its comparator.

Arm/Group Title	SIAC 30 (B)	SIAC 45 (B)	Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	59	59	60
Week 0 (Baseline), N=59, 59, 60	73 (10)	75 (10)	75 (9)
Week 16, N=56, 53, 58	71 (10)	69 (9)	71 (11)

13. Secondary Outcome

Title	Physical Examination
Description	Physical examination is performed at baseline (Week 0) and after 8 and 16 weeks of treatment. If any new findings or deterioration in previous findings were observed during the trial, these were recorded as AEs and are therefore not presented separately as no analysis was performed.
Time Frame	Week 0, Week 8, Week 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Insulin Glargine	SIAC 30 (B)	SIAC 45 (B)
Arm/Group Description	Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.	Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
Measure Participants	0	0	0

Adverse Events

Time Frame	The adverse events were collected in a time frame of 16 weeks + 7 days follow up
Adverse Event Reporting Description	The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Arm/Group Title	SIAC 30 (B)		SIAC 45 (B)		Insulin Glargine
Arm/Group Description	Soluble insulin analogue combination 30 (SIAC 30, 70 volume percent insulin degludec, 600 nmol/ml and 30 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.		Soluble insulin analogue combination 45 (SIAC 45, 55 volume percent insulin degludec, 600 nmol/ml and 45 volume percent insulin aspart, 600 nmol/ml; formulation B) was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.		Insulin glargine was given subcutaneously once daily (OD) before dinner in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were individually adjusted.
All Cause Mortality
	SIAC 30 (B)		SIAC 45 (B)		Insulin Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	SIAC 30 (B)		SIAC 45 (B)		Insulin Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/59 (3.4%)		1/59 (1.7%)		0/60 (0%)
Nervous system disorders
Transient ischaemic attack	1/59 (1.7%)	1	0/59 (0%)	0	0/60 (0%)	0
Psychiatric disorders
Depression	1/59 (1.7%)	1	0/59 (0%)	0	0/60 (0%)	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/59 (0%)	0	1/59 (1.7%)	1	0/60 (0%)	0
Other (Not Including Serious) Adverse Events
	SIAC 30 (B)		SIAC 45 (B)		Insulin Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/59 (39%)		16/59 (27.1%)		13/60 (21.7%)
Gastrointestinal disorders
Dyspepsia	3/59 (5.1%)	4	2/59 (3.4%)	2	1/60 (1.7%)	1
Nausea	1/59 (1.7%)	1	3/59 (5.1%)	3	0/60 (0%)	0
Infections and infestations
Influenza	0/59 (0%)	0	2/59 (3.4%)	2	3/60 (5%)	3
Nasopharyngitis	4/59 (6.8%)	4	3/59 (5.1%)	3	1/60 (1.7%)	3
Investigations
C-reactive protein increased	14/59 (23.7%)	14	5/59 (8.5%)	5	9/60 (15%)	9
Metabolism and nutrition disorders
Dyslipidaemia	6/59 (10.2%)	6	4/59 (6.8%)	4	6/60 (10%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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. Any such communication must be submitted in writing to the Novo Nordisk trial manager prior to submission for comments. Comments will be given within four weeks from receipt of the planned communication.