The Effect of Insulin Degludec in Combination With Liraglutide and Metformin in Subjects With Type 2 Diabetes Qualifying for Treatment Intensification

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01664247
• Collaborator: (none)
• Enrollment: 346
• Locations: 132
• Arms: 2
• Actual Duration (Months): 15
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This trial is conducted in Africa, Asia, Europe and North America. The purpose of the trial is to investigate the effect of insulin degludec (IDeg) in combination with liraglutide (Lira) and metformin (at least 1500 mg daily or maximum tolerated dose) in subjects with type 2 diabetes qualifying for treatment intensification.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 346 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: The Effect of Insulin Degludec in Combination With Liraglutide and Metformin in Subjects With Type 2 Diabetes Qualifying for Treatment Intensification
• Actual Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Dec 31, 2013
• Actual Study Completion Date: Dec 31, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IDeg + Lira	Drug: insulin degludec; Administered s.c. (under the skin) once daily. Dose individually adjusted.; Drug: liraglutide; Administered s.c. (under the skin) once daily. Dose: 1.8 mg.
Experimental: Placebo + Lira	Drug: placebo; Administered s.c. (under the skin) once daily. Dose individually adjusted.; Drug: liraglutide; Administered s.c. (under the skin) once daily. Dose: 1.8 mg.

Outcome Measures

Primary Outcome Measures

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

   Change from baseline in HbA1c after 26 weeks of treatment

Secondary Outcome Measures

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

   Change from baseline in FPG after 26 weeks of treatment

2. Number of Responders for HbA1c (Below 7.0 %) [After 26 weeks of randomised treatment.]

   Number of responders for HbA1c below 7.0%, after 26 weeks of randomised treatment.

3. Change From Baseline in Mean Pre-breakfast Measurements Used for Titration [Week 0, week 26]

   Change from baseline after 26 weeks of treatment in the average of the pre-breakfast self measured plasma glucose (SMPG) measured on the day of the contact and the two days immediately prior to the contact. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline.

4. Change From Baseline in 8-point Profile [Week 0, week 26]

   The change from baseline in the 8-point SMPG profile after 26 weeks of randomised treatment. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline.

5. Change From Baseline in Mean of the 8-point Profile [Week 0, week 26]

   Change from baseline in mean of the 8-point profile after 26 weeks of randomised treatment.

6. Number of Hypoglycaemic Episodes [Weeks 0 - 26]

   Number of confirmed hypoglycaemic episodes from week 0 to 26 weeks of randomised treatment. A hypoglycaemic episode was defined as treatment emergent if the onset of the episode occurred after the first administration of investigational medicinal product and no later than 7 days after the last day on trial product. Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia or minor hypoglycaemic episodes.

7. Number of Adverse Events [Weeks 0 - 26]

   Number of treatment emergent AEs (TEAEs) from week 0 to week 26 of the randomised treatment. A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.

8. Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2) [Week 0, week 26]

   Change in subject's quality of life was evaluated using the Short-Form 36 Health Survey version 2 (SF-36®v2). Evaluations were performed at baseline and at the last treatment visit (week 26). SF-36 was assessed on a scale range of 0.65 to 80.73 for physical health and -8.81 to 81.65 for mental health respectively, where higher scores indicated a better quality of life. 0-100 scores from the SF-36 were converted to a norm-based score using a T-score transformation in order to obtain a direct interpretation in relation to the distribution of the scores in the 1998 U.S. general population.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Type 2 diabetes

• Insulin naïve

• Ongoing treatment with metformin or metformin in combination with either sulphonylurea (SU), glinides, dipeptidyl peptidase-IV (DPP-IV) inhibitors or exenatide (only twice daily (BID))

• Glycosylated haemoglobin (HbA1c) (by central laboratory analysis): a. 7.5-10.0 % (both inclusive) for subjects on metformin monotherapy, b. 7.0-9.0 % (both inclusive) for subjects on metformin in combination with either SU, glinides, DPP-IV inhibitors or exenatide (only BID)

Exclusion Criteria:

• Treatment with glucose-lowering agent(s) other than stated in the inclusion criteria within 12 weeks

• Calcitonin equal to or above 50 pg/mL

• Stroke; heart failure New York Heart Association (NYHA) class III or IV; myocardial infarction; unstable angina pectoris; or coronary arterial bypass graft or angioplasty; all within 24 weeks

• Current or past (within the last 5 years) malignant neoplasms (except basal cell and squamous cell carcinoma)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Anaheim	California	United States	92801
2	Novo Nordisk Investigational Site	Concord	California	United States	94520
3	Novo Nordisk Investigational Site	Escondido	California	United States	92025
4	Novo Nordisk Investigational Site	Fresno	California	United States	93720
5	Novo Nordisk Investigational Site	Huntington Beach	California	United States	92648
6	Novo Nordisk Investigational Site	La Jolla	California	United States	92037
7	Novo Nordisk Investigational Site	Los Angeles	California	United States	90057
8	Novo Nordisk Investigational Site	Monterey	California	United States	93940
9	Novo Nordisk Investigational Site	Spring Valley	California	United States	91978
10	Novo Nordisk Investigational Site	Walnut Creek	California	United States	94598
11	Novo Nordisk Investigational Site	Boynton Beach	Florida	United States	33472
12	Novo Nordisk Investigational Site	Clearwater	Florida	United States	33765
13	Novo Nordisk Investigational Site	Hollywood	Florida	United States	33021
14	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32207
15	Novo Nordisk Investigational Site	Miami	Florida	United States	33135
16	Novo Nordisk Investigational Site	Miami	Florida	United States	33156
17	Novo Nordisk Investigational Site	New Port Richey	Florida	United States	34652
18	Novo Nordisk Investigational Site	Palm Harbor	Florida	United States	34684
19	Novo Nordisk Investigational Site	Tampa	Florida	United States	33603
20	Novo Nordisk Investigational Site	Decatur	Georgia	United States	30033
21	Novo Nordisk Investigational Site	Perry	Georgia	United States	31069
22	Novo Nordisk Investigational Site	Roswell	Georgia	United States	30076
23	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60607
24	Novo Nordisk Investigational Site	Springfield	Illinois	United States	62711
25	Novo Nordisk Investigational Site	Topeka	Kansas	United States	66606
26	Novo Nordisk Investigational Site	Paducah	Kentucky	United States	42003
27	Novo Nordisk Investigational Site	Metairie	Louisiana	United States	70002
28	Novo Nordisk Investigational Site	Hyattsville	Maryland	United States	20782
29	Novo Nordisk Investigational Site	Buckley	Michigan	United States	49620
30	Novo Nordisk Investigational Site	Chesterfield	Missouri	United States	63017-3632
31	Novo Nordisk Investigational Site	Henderson	Nevada	United States	89052-2649
32	Novo Nordisk Investigational Site	Nashua	New Hampshire	United States	03063
33	Novo Nordisk Investigational Site	Lawrenceville	New Jersey	United States	08648
34	Novo Nordisk Investigational Site	Toms River	New Jersey	United States	08755-8050
35	Novo Nordisk Investigational Site	Northport	New York	United States	11768
36	Novo Nordisk Investigational Site	Smithtown	New York	United States	11787
37	Novo Nordisk Investigational Site	West Seneca	New York	United States	14224
38	Novo Nordisk Investigational Site	Chapel Hill	North Carolina	United States	27517
39	Novo Nordisk Investigational Site	Greensboro	North Carolina	United States	27408
40	Novo Nordisk Investigational Site	Morehead City	North Carolina	United States	28557
41	Novo Nordisk Investigational Site	Cincinnati	Ohio	United States	45255
42	Novo Nordisk Investigational Site	Dayton	Ohio	United States	45439
43	Novo Nordisk Investigational Site	Franklin	Ohio	United States	45005
44	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19152
45	Novo Nordisk Investigational Site	Greer	South Carolina	United States	29651
46	Novo Nordisk Investigational Site	Simpsonville	South Carolina	United States	29681
47	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37404-1192
48	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37411
49	Novo Nordisk Investigational Site	Humboldt	Tennessee	United States	38343
50	Novo Nordisk Investigational Site	Kingsport	Tennessee	United States	37660
51	Novo Nordisk Investigational Site	Nashville	Tennessee	United States	37212
52	Novo Nordisk Investigational Site	Austin	Texas	United States	78731
53	Novo Nordisk Investigational Site	Dallas	Texas	United States	75230
54	Novo Nordisk Investigational Site	Dallas	Texas	United States	75231
55	Novo Nordisk Investigational Site	Dallas	Texas	United States	75246
56	Novo Nordisk Investigational Site	Dallas	Texas	United States	75390
57	Novo Nordisk Investigational Site	Houston	Texas	United States	77030-2703
58	Novo Nordisk Investigational Site	Irving	Texas	United States	75061-2210
59	Novo Nordisk Investigational Site	Lubbock	Texas	United States	79423
60	Novo Nordisk Investigational Site	Round Rock	Texas	United States	78681
61	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78224
62	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77478
63	Novo Nordisk Investigational Site	Saint George	Utah	United States	84790
64	Novo Nordisk Investigational Site	Salt Lake City	Utah	United States	84107
65	Novo Nordisk Investigational Site	Newport News	Virginia	United States	23606
66	Novo Nordisk Investigational Site	Spokane	Washington	United States	99218
67	Novo Nordisk Investigational Site	Milwaukee	Wisconsin	United States	53209
68	Novo Nordisk Investigational Site	Delta	British Columbia	Canada	V4K 2K5
69	Novo Nordisk Investigational Site	Brampton	Ontario	Canada	L6T 0G1
70	Novo Nordisk Investigational Site	London	Ontario	Canada	N6P 1A9
71	Novo Nordisk Investigational Site	Ottawa	Ontario	Canada	K1N 1A2
72	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5C 2T2
73	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M9V 4B4
74	Novo Nordisk Investigational Site	Quebec		Canada	G3K 2P8
75	Novo Nordisk Investigational Site	Bron		France	69677
76	Novo Nordisk Investigational Site	Corbeil Essonnes		France	91106
77	Novo Nordisk Investigational Site	Le Creusot		France	71200
78	Novo Nordisk Investigational Site	Merignac		France	33700
79	Novo Nordisk Investigational Site	Nanterre		France	92014
80	Novo Nordisk Investigational Site	Niort		France	79021
81	Novo Nordisk Investigational Site	Pau		France	64000
82	Novo Nordisk Investigational Site	Pointe à Pitre		France	97159
83	Novo Nordisk Investigational Site	Saint Herblain		France	44800
84	Novo Nordisk Investigational Site	Saint-denis de La Reunion		France	97405
85	Novo Nordisk Investigational Site	Venissieux		France	69200
86	Novo Nordisk Investigational Site	Berlin		Germany	12163
87	Novo Nordisk Investigational Site	Falkensee		Germany	14612
88	Novo Nordisk Investigational Site	Friedrichsthal		Germany	66299
89	Novo Nordisk Investigational Site	Hamburg		Germany	22607
90	Novo Nordisk Investigational Site	Hohenmölsen		Germany	06679
91	Novo Nordisk Investigational Site	Kirn		Germany	55606
92	Novo Nordisk Investigational Site	Ludwigshafen		Germany	67059
93	Novo Nordisk Investigational Site	St. Ingbert		Germany	66386
94	Novo Nordisk Investigational Site	Völklingen		Germany	66333
95	Novo Nordisk Investigational Site	Beer Sheva		Israel	84101
96	Novo Nordisk Investigational Site	Haifa		Israel	31096
97	Novo Nordisk Investigational Site	Holon		Israel	58100
98	Novo Nordisk Investigational Site	Jerusalem		Israel	91120
99	Novo Nordisk Investigational Site	Rishon Le Zion		Israel	75650
100	Novo Nordisk Investigational Site	Tel Hashomer		Israel	52621
101	Novo Nordisk Investigational Site	Bologna		Italy	40138
102	Novo Nordisk Investigational Site	Catanzaro		Italy	88100
103	Novo Nordisk Investigational Site	Milano		Italy	20132
104	Novo Nordisk Investigational Site	Roma		Italy	00128
105	Novo Nordisk Investigational Site	Roma		Italy	00133
106	Novo Nordisk Investigational Site	Roma		Italy	00161
107	Novo Nordisk Investigational Site	Verona		Italy	37126
108	Novo Nordisk Investigational Site	Belgrade		Serbia	11000
109	Novo Nordisk Investigational Site	Belgrade		Serbia	11080
110	Novo Nordisk Investigational Site	Kragujevac		Serbia	34000
111	Novo Nordisk Investigational Site	Novi Sad		Serbia	21000
112	Novo Nordisk Investigational Site	Port Elizabeth	Eastern Cape	South Africa	6014
113	Novo Nordisk Investigational Site	Johannesburg	Gauteng	South Africa	1818
114	Novo Nordisk Investigational Site	Johannesburg	Gauteng	South Africa	2198
115	Novo Nordisk Investigational Site	Durban	KwaZulu-Natal	South Africa	4092
116	Novo Nordisk Investigational Site	Cape Town	Western Cape	South Africa	7130
117	Novo Nordisk Investigational Site	Cape Town	Western Cape	South Africa	7700
118	Novo Nordisk Investigational Site	Kharkiv		Ukraine	61000
119	Novo Nordisk Investigational Site	Kiev		Ukraine	04114
120	Novo Nordisk Investigational Site	Lviv		Ukraine	79010
121	Novo Nordisk Investigational Site	Ternopil		Ukraine	46002
122	Novo Nordisk Investigational Site	Vinnitsa		Ukraine	21010
123	Novo Nordisk Investigational Site	Abu Dhabi		United Arab Emirates	51900
124	Novo Nordisk Investigational Site	Dubai		United Arab Emirates	4545
125	Novo Nordisk Investigational Site	Ras Al Khaimah		United Arab Emirates	4727
126	Novo Nordisk Investigational Site	Sharjah		United Arab Emirates	3500
127	Novo Nordisk Investigational Site	Birmingham		United Kingdom	B9 5SS
128	Novo Nordisk Investigational Site	Bristol		United Kingdom	BS10 5NB
129	Novo Nordisk Investigational Site	Coventry		United Kingdom	CV2 2DX
130	Novo Nordisk Investigational Site	London		United Kingdom	SE1 9RT
131	Novo Nordisk Investigational Site	London		United Kingdom	W6 7HY
132	Novo Nordisk Investigational Site	Stevenage		United Kingdom	SG1 4AB

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: NCT01664247
• Other Study ID Numbers: NN1250-3944; 2011-004665-32; U1111-1124-6612
• First Posted: Aug 14, 2012
• Last Update Posted: Sep 25, 2017
• Last Verified: Aug 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Liraglutide

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 129 sites in 11 countries randomised subjects: Canada (7), France (10), Germany (8), Israel (6), Italy (7), Serbia (7), South Africa (6), Ukraine (4), United Arab Emirates (3), United Kingdom (6), and United States (65).

Arm/Group Title	IDeg	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Period Title: Overall Study
STARTED	174	172
Exposed	173	170
COMPLETED	160	131
NOT COMPLETED	14	41

Baseline Characteristics

Arm/Group Title	IDeg	Placebo	Total
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Total of all reporting groups
Overall Participants	174	172	346
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.0 (10.0)	57.3 (9.4)	57.2 (9.7)
Sex: Female, Male (Count of Participants)
Female	76 43.7%	68 39.5%	144 41.6%
Male	98 56.3%	104 60.5%	202 58.4%
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	7.5 (0.6)	7.6 (0.6)	7.6 (0.6)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	8.7 (2.1)	9.1 (2.2)	8.9 (2.2)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%)
Description	Change from baseline in HbA1c after 26 weeks of treatment
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	IDeg	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Measure Participants	174	172
Least Squares Mean (Standard Error) [percentage of glycosylated haemoglobin]	-0.99 (0.08)	-0.07 (0.08)

2. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG)
Description	Change from baseline in FPG after 26 weeks of treatment
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects and missing data was imputed using LOCF. For 6 subjects FPG values were missing.

Arm/Group Title	IDeg	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Measure Participants	172	168
Mean (Standard Deviation) [mmol/L]	-2.60 (2.91)	-0.28 (2.44)

3. Secondary Outcome

Title	Number of Responders for HbA1c (Below 7.0 %)
Description	Number of responders for HbA1c below 7.0%, after 26 weeks of randomised treatment.
Time Frame	After 26 weeks of randomised treatment.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	IDeg	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Measure Participants	174	172
Number [percentage (%) of subjects]	77.6	35.5

4. Secondary Outcome

Title	Change From Baseline in Mean Pre-breakfast Measurements Used for Titration
Description	Change from baseline after 26 weeks of treatment in the average of the pre-breakfast self measured plasma glucose (SMPG) measured on the day of the contact and the two days immediately prior to the contact. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects and missing data was imputed using LOCF. For 8 subjects the baseline values were missing

Arm/Group Title	IDeg	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Measure Participants	171	167
Least Squares Mean (Standard Error) [mmol/L]	5.88 (0.14)	8.23 (0.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IDeg, Placebo
	Comments	The pre-breakfast measures of SMPG values after 26 weeks of treatment were analysed an ANOVA method with treatment, region and sex as fixed effects, and age and baseline response as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.34
	Confidence Interval	(2-Sided) 95%; -2.67 to -2.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment contrast estimated was IDeg - Placebo.

5. Secondary Outcome

Title	Change From Baseline in 8-point Profile
Description	The change from baseline in the 8-point SMPG profile after 26 weeks of randomised treatment. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. The subjects not analysed were 12, 45, 46, 44, 44, 54, 56 and 21 subjects for before breakfast, 90 mins after breakfast, before lunch, 90 mins after start of lunch, before main evening meal, 90 mins after main evening meal, before bedtime and before breakfast the following day time points respectively.

Arm/Group Title	IDeg	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Measure Participants	172	169
Before breakfast, N=170, 164	5.85 (0.15)	8.54 (0.16)
90 min after breakfast, N=153, 148	7.65 (0.24)	9.75 (0.25)
Before lunch, N=151,149	6.33 (0.18)	8.34 (0.19)
90 min after lunch, N=152,150	7.73 (0.21)	9.67 (0.21)
Before evening meal, N=154,148	6.77 (0.20)	9.51 (0.21)
90 mins after evening meal, N=147,145	7.93 (0.21)	9.65 (0.22)
Before bedtime, N=148, 142	7.21 (0.20)	8.95 (0.21)
Before breakfast the next day, N=164,161	6.05 (0.17)	8.55 (0.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IDeg, Placebo
	Comments	The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point before breakfast.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.69
	Confidence Interval	(2-Sided) 95%; -3.04 to -2.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment contrast estimated was IDeg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	IDeg, Placebo
	Comments	The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point 90 mins after breakfast.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.09
	Confidence Interval	(2-Sided) 95%; -2.71 to -1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment contrast estimated was IDeg - Placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	IDeg, Placebo
	Comments	The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point before lunch.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.01
	Confidence Interval	(2-Sided) 95%; -2.47 to -1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment contrast estimated was IDeg - Placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	IDeg, Placebo
	Comments	The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point 90 mins after start of lunch.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-1.93
	Confidence Interval	(2-Sided) 95%; -2.46 to -1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment contrast estimated was IDeg - Placebo.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	IDeg, Placebo
	Comments	The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point main evening meal.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.74
	Confidence Interval	(2-Sided) 95%; -2.25 to -1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment contrast estimated was IDeg - Placebo.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	IDeg, Placebo
	Comments	The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point 90 mins after main evening meal.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.72
	Confidence Interval	(2-Sided) 95%; -2.26 to -1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment contrast estimated was IDeg - Placebo.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	IDeg, Placebo
	Comments	The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point before bedtime.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.75
	Confidence Interval	(2-Sided) 95%; -2.27 to -1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment contrast estimated was IDeg - Placebo.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	IDeg, Placebo
	Comments	The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point before breakfast the following day.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.50
	Confidence Interval	(2-Sided) 95%; -2.91 to -2.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment contrast estimated was IDeg - Placebo.

6. Secondary Outcome

Title	Change From Baseline in Mean of the 8-point Profile
Description	Change from baseline in mean of the 8-point profile after 26 weeks of randomised treatment.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects and missing data is imputed using LOCF. Mean values were missing for 11 subjects.

Arm/Group Title	IDeg	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Measure Participants	169	166
Mean (Standard Deviation) [mmol/L]	-2.3 (1.8)	-0.5 (1.7)

7. Secondary Outcome

Title	Number of Hypoglycaemic Episodes
Description	Number of confirmed hypoglycaemic episodes from week 0 to 26 weeks of randomised treatment. A hypoglycaemic episode was defined as treatment emergent if the onset of the episode occurred after the first administration of investigational medicinal product and no later than 7 days after the last day on trial product. Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia or minor hypoglycaemic episodes.
Time Frame	Weeks 0 - 26

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	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Measure Participants	173	170
Number [events]	47	9

8. Secondary Outcome

Title	Number of Adverse Events
Description	Number of treatment emergent AEs (TEAEs) from week 0 to week 26 of the randomised treatment. A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.
Time Frame	Weeks 0 - 26

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	IDeg	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Measure Participants	173	170
Number [events]	285	252

9. Secondary Outcome

Title	Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2)
Description	Change in subject's quality of life was evaluated using the Short-Form 36 Health Survey version 2 (SF-36®v2). Evaluations were performed at baseline and at the last treatment visit (week 26). SF-36 was assessed on a scale range of 0.65 to 80.73 for physical health and -8.81 to 81.65 for mental health respectively, where higher scores indicated a better quality of life. 0-100 scores from the SF-36 were converted to a norm-based score using a T-score transformation in order to obtain a direct interpretation in relation to the distribution of the scores in the 1998 U.S. general population.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects and missing data was imputed using LOCF. For 3 subjects PRO scores were missing at the baseline and did not contribute to the analysis.

Arm/Group Title	IDeg	Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Measure Participants	174	169
Physical health	0.5 (6.3)	0.0 (6.2)
Mental health	0.6 (8.1)	-0.7 (8.8)

Adverse Events

Time Frame	The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.
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		Placebo
Arm/Group Description	Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.		Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
All Cause Mortality
	IDeg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	IDeg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/173 (3.5%)		9/170 (5.3%)
Cardiac disorders
Atrial fibrillation	0/173 (0%)	0	1/170 (0.6%)	1
Cardiac failure	0/173 (0%)	0	1/170 (0.6%)	1
Cardiac failure congestive	0/173 (0%)	0	1/170 (0.6%)	1
Tachycardia	0/173 (0%)	0	1/170 (0.6%)	1
Ventricular tachycardia	0/173 (0%)	0	1/170 (0.6%)	1
Gastrointestinal disorders
Abdominal hernia	1/173 (0.6%)	1	0/170 (0%)	0
Gastritis erosive	1/173 (0.6%)	1	0/170 (0%)	0
Infections and infestations
Upper respiratory tract infection	0/173 (0%)	0	1/170 (0.6%)	1
Urosepsis	0/173 (0%)	0	1/170 (0.6%)	1
Injury, poisoning and procedural complications
Humerus fracture	0/173 (0%)	0	1/170 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lentigo maligna stage II	1/173 (0.6%)	1	0/170 (0%)	0
Malignant melanoma	0/173 (0%)	0	1/170 (0.6%)	1
Transitional cell carcinoma	0/173 (0%)	0	1/170 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/173 (0%)	0	1/170 (0.6%)	1
Surgical and medical procedures
Cholecystectomy	1/173 (0.6%)	1	0/170 (0%)	0
Diabetes mellitus management	1/173 (0.6%)	1	0/170 (0%)	0
Medical device removal	1/173 (0.6%)	1	0/170 (0%)	0
Vascular disorders
Aortic stenosis	1/173 (0.6%)	1	0/170 (0%)	0
Femoral artery occlusion	1/173 (0.6%)	1	0/170 (0%)	0
Peripheral artery stenosis	1/173 (0.6%)	1	0/170 (0%)	0
Other (Not Including Serious) Adverse Events
	IDeg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/173 (19.1%)		32/170 (18.8%)
Gastrointestinal disorders
Diarrhoea	10/173 (5.8%)	10	13/170 (7.6%)	17
Infections and infestations
Nasopharyngitis	14/173 (8.1%)	15	11/170 (6.5%)	12
Investigations
Lipase increased	10/173 (5.8%)	11	13/170 (7.6%)	15

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.