Comparison of Two NN1250 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: NCT00611884
• Collaborator: (none)
• Enrollment: 245
• Locations: 29
• Arms: 4
• Duration (Months): 7
• Patients Per Site: 8.4
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This trial is conducted in Africa, Asia and North America. The aim of this trial is to compare two insulin degludec (NN1250, SIBA) 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 glargine; Drug: insulin degludec; Drug: insulin degludec; Drug: insulin degludec; Drug: metformin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 245 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 16 Week Randomised, Open-labelled, Four-armed, Treat-to-target, Parallel-group Trial Comparing SIBA D Once Daily, SIBA E Once Daily, SIBA D Monday, Wednesday and Friday and Insulin Glargine Once Daily, 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: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SIBA (D)	Drug: insulin degludec; Formulation D: Treat-to-target dose titration scheme, s.c. injection, once daily; Drug: metformin; Tablets, 1500-2000 mg/day
Experimental: SIBA (E)	Drug: insulin degludec; Formulation E: Treat-to-target dose titration scheme, s.c. injection, once daily; Drug: metformin; Tablets, 1500-2000 mg/day
Experimental: SIBA (D) M, W, F	Drug: insulin degludec; Formulation D: Treat-to-target dose titration scheme, s.c. injection, 3 times weekly; Drug: metformin; Tablets, 1500-2000 mg/day
Active Comparator: IGlar	Drug: insulin glargine; Treat-to-target dose titration scheme, s.c. injection.; 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. 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, before bedtime, at 4 am and before breakfast.

2. 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.

3. 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 05:59 (included).

4. 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.

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

   Mean values at Week -4 and at Week 16

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

   Mean values at Week -4 and at Week 16

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

   Mean values at Week -4 and at Week 16

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

   Mean values at baseline (Week 0) and at Week 16

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

   Mean values at baseline (Week 0) and at Week 16

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

    Mean values at baseline (Week 0) and at Week 16

11. Physical Examination [Week -4, Week 0, Week 8, Week 16]

    Physical examination was performed at screening (Week -4), randomisation (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 maximeum 14 days within the last 3 months)

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

• HbA1c 7.0-11.0 % (both inclusive)

• Body Mass Index (BMI) 23-42 kg/m^{2 [lb/in}2 x 703] (both inclusive)

Exclusion Criteria:

• Metformin contraindication according to local practice

• Thiazolidinedione (TZD) treatment within 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) three 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 (except for conditions associated with type 2 diabetes) that, in the opinion of the Investigator, may confound the results of the trial or pose additional risk in administering trial drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Inglewood	California	United States	90301
2	Novo Nordisk Investigational Site	Los Angeles	California	United States	90057
3	Novo Nordisk Investigational Site	Redlands	California	United States	92374
4	Novo Nordisk Investigational Site	Spring Valley	California	United States	91978
5	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32204
6	Novo Nordisk Investigational Site	Idaho Falls	Idaho	United States	83404-7596
7	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60607
8	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60616
9	Novo Nordisk Investigational Site	Springfield	Illinois	United States	62711
10	Novo Nordisk Investigational Site	Greensboro	North Carolina	United States	27408
11	Novo Nordisk Investigational Site	Medford	Oregon	United States	97504
12	Novo Nordisk Investigational Site	Simpsonville	South Carolina	United States	29681
13	Novo Nordisk Investigational Site	Kingsport	Tennessee	United States	37660
14	Novo Nordisk Investigational Site	Dallas	Texas	United States	75230
15	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78229
16	Novo Nordisk Investigational Site	Newport News	Virginia	United States	23606
17	Novo Nordisk Investigational Site	Renton	Washington	United States	98057
18	Novo Nordisk Investigational Site	Milwaukee	Wisconsin	United States	53209
19	Novo Nordisk Investigational Site	Cambridge	Ontario	Canada	N1R 7L6
20	Novo Nordisk Investigational Site	Etobicoke	Ontario	Canada	M9R 4E1
21	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5C 2T2
22	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5T 3L9
23	Novo Nordisk Investigational Site	Hyderabad	Andhra Pradesh	India	500082
24	Novo Nordisk Investigational Site	Kochi	Kerala	India	682041
25	Novo Nordisk Investigational Site	Mumbai	Maharashtra	India	400012
26	Novo Nordisk Investigational Site	Vellore	Tamil Nadu	India	632004
27	Novo Nordisk Investigational Site	Johannesburg	Gauteng	South Africa	2001
28	Novo Nordisk Investigational Site	Durban	KwaZulu-Natal	South Africa	4001
29	Novo Nordisk Investigational Site	Durban	KwaZulu-Natal	South Africa	4126

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: NCT00611884
• Other Study ID Numbers: NN1250-1836
• First Posted: Feb 11, 2008
• Last Update Posted: Mar 3, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Metformin; Insulin Glargine; Insulin, Long-Acting

Study Results

Participant Flow

Recruitment Details	There were 28 sites: Canada (4), India (4), South Africa (3) and the United States of America (17).
Pre-assignment Detail	Subjects underwent a run-in period of 3 weeks; 2 weeks of up-titration period, where metformin was up-titrated to 1500 or 2000 mg/day, followed by 1 week of maintenance period. Subjects who tolerated 1500 or 2000 mg/day of metformin for a week and had a median fasting plasma glucose ≥ 7.5 mmol/L (135 mg/dL) were randomised.

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Period Title: Overall Study
STARTED	61	60	62	62
Exposed	58	59	61	61
COMPLETED	52	51	58	56
NOT COMPLETED	9	9	4	6

Baseline Characteristics

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar	Total
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Total of all reporting groups
Overall Participants	61	60	62	62	245
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.9 (8.5)	55.3 (8.7)	54.4 (8.8)	53.1 (10.2)	54.2 (9.1)
Sex: Female, Male (Count of Participants)
Female	22 36.1%	27 45%	34 54.8%	25 40.3%	108 44.1%
Male	39 63.9%	33 55%	28 45.2%	37 59.7%	137 55.9%
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.7 (1.1)	8.6 (1.2)	8.8 (1.1)	8.7 (1.1)	8.7 (1.1)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	10.6 (3.6)	9.9 (3.2)	10.6 (3.4)	9.8 (3.1)	10.2 (3.4)

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

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

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	61	60	62	62
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	-1.26 (1.11)	-1.28 (1.11)	-1.46 (1.06)	-1.49 (1.12)

2. 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, before bedtime, at 4 am and before breakfast.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	61	60	62	62
Least Squares Mean (Standard Error) [mmol/L]	8.30 (0.42)	8.55 (0.42)	8.45 (0.42)	8.42 (0.41)

3. 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 full analysis set (FAS) included all randomised subjects.

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	61	60	62	62
Major	0	0	6	0
Minor	89	60	221	113

4. 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 05:59 (included).
Time Frame	Week 0 to Week 16 + 5 days follow up

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) included all randomised subjects.

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	61	60	62	62
Major	0	0	6	0
Minor	6	12	17	0

5. 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

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

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	57	59	62	61
Adverse events (AEs)	594	430	488	622
Serious AEs	6	0	5	0
Severe AEs	12	6	0	28
Moderate AEs	114	102	110	141
Mild AEs	468	323	379	452
Fatal	0	0	0	0

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	57	59	62	61
ALAT, Week -4, N=56, 59, 62, 60	34.6 (19.9)	29.2 (16.3)	30.9 (16.0)	32.9 (22.0)
ALAT, Week 16, N=53, 53, 58, 56	25.7 (13.1)	24.7 (14.4)	24.3 (13.0)	30.0 (25.3)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	57	59	62	61
ASAT, Week -4, N=56, 59, 62, 60	26.7 (13.6)	22.5 (9.9)	23.9 (8.5)	24.2 (12.6)
ASAT, Week 16, N=53, 53, 58, 56	23.3 (10.0)	21.8 (7.7)	21.7 (7.7)	24.1 (13.7)

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	57	59	62	61
Creatinine, Week -4, N=56, 59, 62, 60	74.5 (15.2)	75.4 (19.0)	73.2 (16.1)	72.4 (13.9)
Creatinine, Week 16, N=53, 53, 58, 56	76.1 (15.9)	76.6 (19.1)	71.5 (15.6)	74.2 (14.4)

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	57	59	62	61
Week 0 (Baseline), N=57, 59, 62, 61	81 (9)	82 (9)	80 (8)	79 (7)
Week 16, N=55, 55, 60, 56	79 (8)	82 (8)	78 (9)	77 (8)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	57	59	62	61
Week 0 (Baseline), N=57, 59, 62, 61	129 (14)	131 (13)	129 (15)	127 (14)
Week 16, N=55, 55, 60, 56	126 (14)	131 (15)	126 (16)	128 (13)

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	57	59	62	61
Week 0 (Baseline), N=57, 59, 62, 61	79 (10)	79 (9)	79 (9)	76 (9)
Week 16, N=55, 55, 60, 56	77 (11)	78 (10)	79 (9)	74 (9)

12. Secondary Outcome

Title	Physical Examination
Description	Physical examination was performed at screening (Week -4), randomisation (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 -4, Week 0, Week 8, Week 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SIBA (D)	SIBA (E)	SIBA (D) M, W, F	IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.	Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.	Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
Measure Participants	0	0	0	0

Adverse Events

Time Frame	The adverse events were collected in a time frame of 16 weeks + 5 days follow up
Adverse Event Reporting Description	Subjects in the safety analysis set contribute to the evaluation "as treated", hence the one subject who was treated with SIBA (D) 3W although he was randomised to SIBA (D) OD is analysed as SIBA (D) 3W for safety and as SIBA (D) OD in the FAS.
Arm/Group Title	SIBA (D)		SIBA (E)		SIBA (D) M, W, F		IGlar
Arm/Group Description	Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL [1 dosing unit = 9 nmol], insulin degludec; formulation D) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 units (U)/day and individually adjusted.		Soluble Insulin Basal Analogue E (SIBA E, 600 nmol/mL (1 dosing unit = 6 nmol), insulin degludec; formulation E) was given subcutaneously once daily (OD) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.		Soluble Insulin Basal Analogue D (SIBA D, 900 nmol/mL (1 dosing unit = 9 nmol), insulin degludec; formulation D) was given subcutaneously thrice weekly (Monday [M], Wednesday[W], Friday[F]) in the evening in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were were initiated at 20 U/day and individually adjusted.		Insulin glargine (IGlar) was given subcutaneously once daily (OD) before bedtime in combination with at least 1500 mg/day metformin (tablets) for 16 weeks. Insulin doses were initiated at 10 U/day and individually adjusted.
All Cause Mortality
	SIBA (D)		SIBA (E)		SIBA (D) M, W, F		IGlar
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	SIBA (D)		SIBA (E)		SIBA (D) M, W, F		IGlar
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/57 (1.8%)		0/59 (0%)		1/62 (1.6%)		0/61 (0%)
Cardiac disorders
Atrial fibrillation	1/57 (1.8%)	1	0/59 (0%)	0	0/62 (0%)	0	0/61 (0%)	0
Coronary artery disease	0/57 (0%)	0	0/59 (0%)	0	1/62 (1.6%)	1	0/61 (0%)	0
Other (Not Including Serious) Adverse Events
	SIBA (D)		SIBA (E)		SIBA (D) M, W, F		IGlar
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/57 (38.6%)		16/59 (27.1%)		19/62 (30.6%)		23/61 (37.7%)
Gastrointestinal disorders
Diarrhoea	3/57 (5.3%)	4	3/59 (5.1%)	3	3/62 (4.8%)	5	6/61 (9.8%)	7
Toothache	3/57 (5.3%)	4	0/59 (0%)	0	2/62 (3.2%)	3	1/61 (1.6%)	1
Infections and infestations
Influenza	1/57 (1.8%)	1	4/59 (6.8%)	4	0/62 (0%)	0	1/61 (1.6%)	1
Nasopharyngitis	2/57 (3.5%)	2	2/59 (3.4%)	2	4/62 (6.5%)	4	7/61 (11.5%)	7
Metabolism and nutrition disorders
Dyslipidaemia	3/57 (5.3%)	3	1/59 (1.7%)	1	0/62 (0%)	0	0/61 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/57 (0%)	0	3/59 (5.1%)	3	2/62 (3.2%)	2	2/61 (3.3%)	2
Back pain	4/57 (7%)	4	0/59 (0%)	0	5/62 (8.1%)	6	3/61 (4.9%)	4
Pain in extremity	3/57 (5.3%)	3	2/59 (3.4%)	2	2/62 (3.2%)	4	3/61 (4.9%)	3
Nervous system disorders
Dizziness	1/57 (1.8%)	1	3/59 (5.1%)	3	0/62 (0%)	0	2/61 (3.3%)	2
Headache	3/57 (5.3%)	3	2/59 (3.4%)	2	5/62 (8.1%)	7	8/61 (13.1%)	9
Paraesthesia	1/57 (1.8%)	1	3/59 (5.1%)	3	0/62 (0%)	0	2/61 (3.3%)	3
Respiratory, thoracic and mediastinal disorders
Cough	1/57 (1.8%)	1	2/59 (3.4%)	2	1/62 (1.6%)	1	5/61 (8.2%)	6
Vascular disorders
Hypertension	3/57 (5.3%)	3	1/59 (1.7%)	2	0/62 (0%)	0	1/61 (1.6%)	1

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.