BEGIN™: Comparison of the Efficacy and Safety of Two Intensification Strategies in Subjects With Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01388361
• Collaborator: (none)
• Enrollment: 413
• Locations: 124
• Arms: 3
• Duration (Months): 10
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This trial is conducted in Europe and North America. The aim of this trial is to compare the efficacy and safety of adding liraglutide versus addition of insulin aspart with the largest meal to insulin degludec in subjects with type 2 diabetes.

Eligible subjects with an HbA1c equal to or above 7% at end of treatment in NN1250-3643 (NCT01193309) trial will be randomised to receive treatment intensification while subjects with an HbA1c below 7% at end of treatment in NN1250-3643 (NCT01193309) may continue to receive insulin degludec treatment. Subjects are to continue their pre-trial metformin treatment.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: insulin degludec; Drug: insulin aspart; Drug: liraglutide	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 413 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Trial Comparing the Efficacy and Safety of Adding Liraglutide Versus Addition of Insulin Aspart With the Largest Meal to Insulin Degludec, Both in Combination With Metformin, in Subjects With Type 2 Diabetes Qualifying for Treatment Intensification (BEGIN™: VICTOZA® ADD-ON)
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IDeg (non-randomised)	Drug: insulin degludec; Injected s.c. (under the skin) once daily. The doses will be individually adjusted
Experimental: IDeg + IAsp	Drug: insulin degludec; Injected s.c. (under the skin) once daily. The doses will be individually adjusted; Drug: insulin aspart; Injected s.c. (under the skin) once daily. The doses will be individually adjusted.
Experimental: IDeg + liraglutide	Drug: insulin degludec; Injected s.c. (under the skin) once daily. The doses will be individually adjusted; Drug: liraglutide; Injected s.c. (under the skin) once daily. The doses will be individually adjusted.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in HbA1c (%) (Glycosylated Haemoglobin) [week 0, week 26]

   Values for change in HbA1c from baseline to 26 weeks of treatment period.

Secondary Outcome Measures

1. Change From Baseline in Fasting Plasma Glucose (FPG) [week 0, week 26]

   Values for change in FPG in mmol/L from baseline to week 26 of randomised period.

2. Change From Baseline in Body Weight [week 0, week 26]

   Corresponds to the values of change in body weight in kilograms from baseline to week 26.

3. Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes [Onset on or after the first day of exposure to investigational product for 26 weeks of treatment period and no later than 7 days after last exposure to investigational product.]

   Corresponds to number of treatment emergent hypoglycaemic events from onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product. Confirmed hypoglycaemia was defined as the pool of severe hypoglycaemic episodes and minor episodes with a plasma glucose (PG) value < 3.1 mmol/L (56 mg/dL).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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).

• The subject must have completed the end of treatment visit of NN1250-3643 with Insulin degludec once daily + metformin.

• Ability and willingness to adhere to the protocol including self measurement of plasma glucose according to the protocol

Exclusion Criteria:

• Participated in NN1250-3643 and treated with insulin glargine

• Previous treatment with glucacon like peptide (GLP-1) receptor agonists (e.g. exenatide, liraglutide)

• Impaired liver function, defined as alanine aminotransferase (ALAT) 2.5 times the upper limit of normal at end of treatment in NN1250-3643

• Impaired renal function defined as serum-creatinine = 125 µmol/l (= 1.4 mg/dl) for males and = 110 µmol/L (= 1.3 mg/dl) for females or according to local label for metformin [For France: glomerular filtration rate below 60 ml/min, calculated by the Cockroft & Gault formula] at end of treatment in NN1250-3643.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Concord	California	United States	94520-1926
2	Novo Nordisk Investigational Site	La Jolla	California	United States	92037
3	Novo Nordisk Investigational Site	Lancaster	California	United States	93534
4	Novo Nordisk Investigational Site	Los Angeles	California	United States	90057
5	Novo Nordisk Investigational Site	National City	California	United States	91950
6	Novo Nordisk Investigational Site	Northridge	California	United States	91325
7	Novo Nordisk Investigational Site	Palm Springs	California	United States	92262
8	Novo Nordisk Investigational Site	Santa Monica	California	United States	90404
9	Novo Nordisk Investigational Site	Spring Valley	California	United States	91978
10	Novo Nordisk Investigational Site	Tarzana	California	United States	91356-3551
11	Novo Nordisk Investigational Site	Tustin	California	United States	92780
12	Novo Nordisk Investigational Site	Boynton Beach	Florida	United States	33472
13	Novo Nordisk Investigational Site	Melbourne	Florida	United States	32901
14	Novo Nordisk Investigational Site	Miami	Florida	United States	33156
15	Novo Nordisk Investigational Site	New Port Richey	Florida	United States	34652
16	Novo Nordisk Investigational Site	Palm Harbor	Florida	United States	34684
17	Novo Nordisk Investigational Site	West Palm Beach	Florida	United States	33401
18	Novo Nordisk Investigational Site	Decatur	Georgia	United States	30033
19	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60607
20	Novo Nordisk Investigational Site	Evansville	Indiana	United States	47714
21	Novo Nordisk Investigational Site	Paducah	Kentucky	United States	42003
22	Novo Nordisk Investigational Site	Metairie	Louisiana	United States	70002
23	Novo Nordisk Investigational Site	Slidell	Louisiana	United States	70461-4231
24	Novo Nordisk Investigational Site	North East	Maryland	United States	21901
25	Novo Nordisk Investigational Site	Rockville	Maryland	United States	20852
26	Novo Nordisk Investigational Site	Toms River	New Jersey	United States	08755-8050
27	Novo Nordisk Investigational Site	Northport	New York	United States	11768
28	Novo Nordisk Investigational Site	Staten Island	New York	United States	10301
29	Novo Nordisk Investigational Site	Asheboro	North Carolina	United States	27203
30	Novo Nordisk Investigational Site	Cincinnati	Ohio	United States	45245
31	Novo Nordisk Investigational Site	Oklahoma City	Oklahoma	United States	73103
32	Novo Nordisk Investigational Site	Melrose Park	Pennsylvania	United States	19027
33	Novo Nordisk Investigational Site	Upper St. Clair	Pennsylvania	United States	15241
34	Novo Nordisk Investigational Site	East Providence	Rhode Island	United States	02914
35	Novo Nordisk Investigational Site	Columbia	South Carolina	United States	29203
36	Novo Nordisk Investigational Site	Greer	South Carolina	United States	29651
37	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37411
38	Novo Nordisk Investigational Site	Humboldt	Tennessee	United States	38343
39	Novo Nordisk Investigational Site	Nashville	Tennessee	United States	37203
40	Novo Nordisk Investigational Site	Arlington	Texas	United States	76014
41	Novo Nordisk Investigational Site	Dallas	Texas	United States	75230
42	Novo Nordisk Investigational Site	Dallas	Texas	United States	75246
43	Novo Nordisk Investigational Site	Fort Worth	Texas	United States	76113
44	Novo Nordisk Investigational Site	Irving	Texas	United States	75061-2210
45	Novo Nordisk Investigational Site	Lubbock	Texas	United States	79423
46	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78215
47	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77479
48	Novo Nordisk Investigational Site	Milwaukee	Wisconsin	United States	53209
49	Novo Nordisk Investigational Site	Feldkirch		Austria	6807
50	Novo Nordisk Investigational Site	Wien		Austria	1030
51	Novo Nordisk Investigational Site	Wien		Austria	1090
52	Novo Nordisk Investigational Site	Wien		Austria	1130
53	Novo Nordisk Investigational Site	Wolfsberg		Austria	9400
54	Novo Nordisk Investigational Site	Brussels		Belgium	1070
55	Novo Nordisk Investigational Site	Gent		Belgium	9000
56	Novo Nordisk Investigational Site	Leuven		Belgium	3000
57	Novo Nordisk Investigational Site	Liège		Belgium	4000
58	Novo Nordisk Investigational Site	Edmonton	Alberta	Canada	T5J 3N4
59	Novo Nordisk Investigational Site	Coquitlam	British Columbia	Canada	V3K 3P4
60	Novo Nordisk Investigational Site	Vancouver	British Columbia	Canada	V5Z 1M9
61	Novo Nordisk Investigational Site	Winnipeg	Manitoba	Canada	R3E 3P4
62	Novo Nordisk Investigational Site	Mount Pearl	Newfoundland and Labrador	Canada	A1N 1W7
63	Novo Nordisk Investigational Site	St. John's	Newfoundland and Labrador	Canada	A1A 3R5
64	Novo Nordisk Investigational Site	Halifax	Nova Scotia	Canada	B3K 0A4
65	Novo Nordisk Investigational Site	Mississauga	Ontario	Canada	L5M 2V8
66	Novo Nordisk Investigational Site	Ottawa	Ontario	Canada	K1K 4L2
67	Novo Nordisk Investigational Site	Ottawa	Ontario	Canada	K1N 6N5
68	Novo Nordisk Investigational Site	Scarborough	Ontario	Canada	M1E 5E9
69	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5C 2T2
70	Novo Nordisk Investigational Site	St-Marc-des-Carrières	Quebec	Canada	G0A 4B0
71	Novo Nordisk Investigational Site	St. Romuald	Quebec	Canada	G6W 5M6
72	Novo Nordisk Investigational Site	Quebec		Canada	G1V 4G2
73	Novo Nordisk Investigational Site	Brno		Czech Republic	65691
74	Novo Nordisk Investigational Site	Hradec Kralove		Czech Republic	500 05
75	Novo Nordisk Investigational Site	Plzen		Czech Republic	304 60
76	Novo Nordisk Investigational Site	Prague 4		Czech Republic	140 21
77	Novo Nordisk Investigational Site	Esbjerg		Denmark	6700
78	Novo Nordisk Investigational Site	Hillerød		Denmark	3400
79	Novo Nordisk Investigational Site	Holbæk		Denmark	4300
80	Novo Nordisk Investigational Site	København S		Denmark	2300
81	Novo Nordisk Investigational Site	Odense		Denmark	5000
82	Novo Nordisk Investigational Site	Silkeborg		Denmark	8600
83	Novo Nordisk Investigational Site	Helsinki		Finland	00260
84	Novo Nordisk Investigational Site	Joensuu		Finland	80100
85	Novo Nordisk Investigational Site	Kerava		Finland	FI-04200
86	Novo Nordisk Investigational Site	Lohja		Finland	08100
87	Novo Nordisk Investigational Site	Oulu		Finland	90100
88	Novo Nordisk Investigational Site	Tampere		Finland	33210
89	Novo Nordisk Investigational Site	Montigny-les-Metz		France	57950
90	Novo Nordisk Investigational Site	Nanterre		France	92014
91	Novo Nordisk Investigational Site	Nimes		France	30006
92	Novo Nordisk Investigational Site	Venissieux		France	69200
93	Novo Nordisk Investigational Site	Berlin		Germany	12163
94	Novo Nordisk Investigational Site	Berlin		Germany	13055
95	Novo Nordisk Investigational Site	Dresden		Germany	01307
96	Novo Nordisk Investigational Site	Essen		Germany	45329
97	Novo Nordisk Investigational Site	Friedrichsthal		Germany	66299
98	Novo Nordisk Investigational Site	Hamburg		Germany	22391
99	Novo Nordisk Investigational Site	Hohenmölsen		Germany	06679
100	Novo Nordisk Investigational Site	Neuwied		Germany	56564
101	Novo Nordisk Investigational Site	Pohlheim		Germany	35415
102	Novo Nordisk Investigational Site	Rehburg-Loccum		Germany	31547
103	Novo Nordisk Investigational Site	Rehlingen-Siersburg		Germany	66780
104	Novo Nordisk Investigational Site	Speyer		Germany	67346
105	Novo Nordisk Investigational Site	St. Ingbert		Germany	66386
106	Novo Nordisk Investigational Site	Bekkestua		Norway	1357
107	Novo Nordisk Investigational Site	Elverum		Norway	2408
108	Novo Nordisk Investigational Site	Hamar		Norway	2318
109	Novo Nordisk Investigational Site	Kongsvinger		Norway	2212
110	Novo Nordisk Investigational Site	Oslo		Norway	0407
111	Novo Nordisk Investigational Site	Stavanger		Norway	4011
112	Novo Nordisk Investigational Site	Trondheim		Norway	NO-7030
113	Novo Nordisk Investigational Site	Ålesund		Norway	6003
114	Novo Nordisk Investigational Site	Belgrade		Serbia	11000
115	Novo Nordisk Investigational Site	Kragujevac		Serbia	34000
116	Novo Nordisk Investigational Site	Nis		Serbia	18000
117	Novo Nordisk Investigational Site	Novi Sad		Serbia	21000
118	Novo Nordisk Investigational Site	Almería		Spain	04001
119	Novo Nordisk Investigational Site	Antequera		Spain	29200
120	Novo Nordisk Investigational Site	El Ferrol		Spain	15405
121	Novo Nordisk Investigational Site	Inca		Spain	07300
122	Novo Nordisk Investigational Site	Palma de Mallorca		Spain	07014
123	Novo Nordisk Investigational Site	Sevilla		Spain	41003
124	Novo Nordisk Investigational Site	Sevilla		Spain	41010

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: NCT01388361
• Other Study ID Numbers: NN1250-3948; 2011-001493-25; U1111-1120-2782
• First Posted: Jul 6, 2011
• Last Update Posted: Mar 6, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Insulin Aspart; Liraglutide

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 119 sites in 12 countries: Austria (4), Belgium (4), Canada (15), Czech Republic (4), Denmark (6), Finland (6), France (4), Germany (12), Norway (6), Serbia (5), Spain (7) and United States (46). These sites enrolled subjects in the randomised or non-randomised arms of the trial.
Pre-assignment Detail	Subjects treated with Insulin degludec (IDeg) once daily (OD) + metformin in trial NN1250-3643 (NCT01193309) were eligible for this trial. Eligible subjects with an HbA1c >/=7.0% at the end of 3643 trial were qualified to enter the extension trial 3948 and be randomised to add either liraglutide/insulin aspart to their prior IDeg + Met treatment.

Arm/Group Title	IDeg	IDeg + Liraglutide	IDeg + IAsp OD
Arm/Group Description	This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) < 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Period Title: Overall Study
STARTED	236	88	89
Exposed	234	87	86
COMPLETED	224	76	75
NOT COMPLETED	12	12	14

Baseline Characteristics

Arm/Group Title	IDeg	IDeg + Liraglutide	IDeg + IAsp OD	Total
Arm/Group Description	This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) < 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	Total of all reporting groups
Overall Participants	236	88	89	413
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.9 (9.3)	NA (NA)	NA (NA)	61.9 (9.3)
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	NA (NA)	61.1 (9.5)	60.9 (8.8)	61.0 (9.2)
Sex: Female, Male (Count of Participants)
Female	90 38.1%	NA NaN	NA NaN	NA NaN
Male	146 61.9%	NA NaN	NA NaN	NA NaN
Sex: Female, Male (Count of Participants)
Female	NA NaN	25 28.4%	36 40.4%	NA NaN
Male	NA NaN	63 71.6%	53 59.6%	NA NaN
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	6.4 (0.4)	NA (NA)	NA (NA)	6.4 (0.4)
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	NA (NA)	7.7 (0.6)	7.7 (0.8)	7.7 (0.7)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	6.7 (1.8)	NA (NA)	NA (NA)	6.7 (1.8)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	NA (NA)	6.4 (2.4)	6.1 (1.7)	6.3 (2.1)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in HbA1c (%) (Glycosylated Haemoglobin)
Description	Values for change in HbA1c from baseline to 26 weeks of treatment period.
Time Frame	week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS and NAS included all randomised and non-randomised subjects respectively, and missing data was imputed using last observation carried forward (LOCF).

Arm/Group Title	IDeg	IDeg + Liraglutide	IDeg + IAsp OD
Arm/Group Description	This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) < 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Measure Participants	236	88	89
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	0.10 (0.40)	-0.74 (0.73)	-0.39 (0.72)

2. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG)
Description	Values for change in FPG in mmol/L from baseline to week 26 of randomised period.
Time Frame	week 0, week 26

Outcome Measure Data

Analysis Population Description

Both sets of FAS and NAS included all randomised and non-randomised subjects in the treatment period. The FPG values were missing for 7 subjects in FAS (2 subjects with IDeg+ liraglutide; 5 subjects with IDeg+IAsp arm) and 10 subjects in NAS for IDeg arm at baseline. The missing data was imputed using LOCF.

Arm/Group Title	IDeg	IDeg + Liraglutide	IDeg + IAsp OD
Arm/Group Description	This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) < 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Measure Participants	226	86	84
Mean (Standard Deviation) [mmol/L]	-1.23 (2.03)	-0.14 (2.52)	-0.04 (2.84)

3. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Corresponds to the values of change in body weight in kilograms from baseline to week 26.
Time Frame	week 0, week 26

Outcome Measure Data

Analysis Population Description

Both sets of FAS and NAS included all randomised and non-randomised subjects in the treatment period and missing data was imputed using LOCF. At baseline, the body weight values were missing for 1 subject in IDeg + Liraglutide arm from FAS and 3 subjects in NAS for IDeg arm.

Arm/Group Title	IDeg	IDeg + Liraglutide	IDeg + IAsp OD
Arm/Group Description	This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) < 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Measure Participants	233	87	89
Mean (Standard Deviation) [kg]	0.1 (2.7)	-1.0 (1.3)	0.3 (0.9)

4. Secondary Outcome

Title	Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes
Description	Corresponds to number of treatment emergent hypoglycaemic events from onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product. Confirmed hypoglycaemia was defined as the pool of severe hypoglycaemic episodes and minor episodes with a plasma glucose (PG) value < 3.1 mmol/L (56 mg/dL).
Time Frame	Onset on or after the first day of exposure to investigational product for 26 weeks of treatment period and no later than 7 days after last exposure to investigational product.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	IDeg	IDeg + Liraglutide	IDeg + IAsp OD
Arm/Group Description	This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) < 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Measure Participants	236	87	86
Confirmed(severe+minor)	313	40	330
Severe	1	0	0

Adverse Events

Time Frame	Treatment emergent adverse events were collected during 26 week treatment period + 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	IDeg		IDeg + Liraglutide		IDeg + IAsp OD
Arm/Group Description	This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) < 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.		All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.		Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
All Cause Mortality
	IDeg		IDeg + Liraglutide		IDeg + IAsp OD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	IDeg		IDeg + Liraglutide		IDeg + IAsp OD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/236 (4.7%)		4/87 (4.6%)		5/86 (5.8%)
Cardiac disorders
Acute myocardial infarction	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Angina pectoris	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Coronary artery disease	0/236 (0%)	0	1/87 (1.1%)	1	0/86 (0%)	0
Eye disorders
Vitreous detachment	0/236 (0%)	0	0/87 (0%)	0	1/86 (1.2%)	1
Gastrointestinal disorders
Gastrooesophageal reflux disease	0/236 (0%)	0	1/87 (1.1%)	1	0/86 (0%)	0
Pancreatitis	0/236 (0%)	0	0/87 (0%)	0	1/86 (1.2%)	1
General disorders
Chest pain	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Non-cardiac chest pain	2/236 (0.8%)	2	0/87 (0%)	0	0/86 (0%)	0
Hepatobiliary disorders
Cholelithiasis	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Infections and infestations
Cellulitis	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Injury, poisoning and procedural complications
Humerus fracture	0/236 (0%)	0	0/87 (0%)	0	1/86 (1.2%)	1
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/236 (0%)	0	0/87 (0%)	0	1/86 (1.2%)	1
Hypoglycaemia	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/236 (0.4%)	2	0/87 (0%)	0	0/86 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/236 (0%)	0	1/87 (1.1%)	1	0/86 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/236 (0%)	0	0/87 (0%)	0	1/86 (1.2%)	1
Syncope	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Renal and urinary disorders
Calculus ureteric	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Glomerulonephritis	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Vascular disorders
Hypertensive crisis	1/236 (0.4%)	1	0/87 (0%)	0	0/86 (0%)	0
Peripheral vascular disorder	0/236 (0%)	0	1/87 (1.1%)	1	0/86 (0%)	0
Other (Not Including Serious) Adverse Events
	IDeg		IDeg + Liraglutide		IDeg + IAsp OD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/236 (27.1%)		40/87 (46%)		18/86 (20.9%)
Gastrointestinal disorders
Diarrhoea	8/236 (3.4%)	10	9/87 (10.3%)	12	1/86 (1.2%)	2
Nausea	3/236 (1.3%)	3	18/87 (20.7%)	25	1/86 (1.2%)	1
Vomiting	4/236 (1.7%)	4	5/87 (5.7%)	5	0/86 (0%)	0
Infections and infestations
Bronchitis	13/236 (5.5%)	14	1/87 (1.1%)	1	2/86 (2.3%)	2
Nasopharyngitis	43/236 (18.2%)	54	9/87 (10.3%)	11	11/86 (12.8%)	12
Upper respiratory tract infection	12/236 (5.1%)	15	4/87 (4.6%)	5	3/86 (3.5%)	3
Investigations
Lipase increased	0/236 (0%)	0	6/87 (6.9%)	7	0/86 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	2/236 (0.8%)	2	5/87 (5.7%)	5	1/86 (1.2%)	1

Limitations/Caveats

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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.