ADJUNCT ONE™: The Efficacy and Safety of Liraglutide as Adjunct Therapy to Insulin in the Treatment of Type 1 Diabetes

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01836523
• Collaborator: (none)
• Enrollment: 1,398
• Locations: 182
• Arms: 6
• Duration (Months): 19
• Patients Per Site: 7.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This trial is conducted globally. The aim of the trial is to confirm the efficacy and safety of liraglutide as adjunct therapy to insulin in the treatment of type 1 diabetes. The total trial duration per subject is approximately 58 weeks.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 1	Drug: liraglutide; Drug: placebo; Drug: liraglutide; Drug: placebo; Drug: liraglutide; Drug: placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1398 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: The Efficacy and Safety of Liraglutide as Adjunct Therapy to Insulin in the Treatment of Type 1 Diabetes. A 52-week Randomised, Treat-to-target, Placebo-controlled, Double Blinded, Parallel Group, Multinational, Multi-centre Trial
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Liraglutide 0.6 mg + insulin	Drug: liraglutide; Subjects randomised to 0.6 mg liraglutide treatment or liraglutide placebo as an add-on to their pre-trial insulin treatment will remain on this dose throughout the study (52 weeks). Administered subcutaneously (s.c., under the skin) once daily.
Experimental: Liraglutide 1.2 mg + insulin	Drug: liraglutide; Subjects randomised to 0.6 mg liraglutide treatment or liraglutide placebo as an add-on to their pre-trial insulin treatment will remain on this dose throughout the study (52 weeks). Administered subcutaneously (s.c., under the skin) once daily.
Experimental: Liraglutide 1.8 mg + insulin	Drug: liraglutide; Subjects randomised to 0.6 mg liraglutide treatment or liraglutide placebo as an add-on to their pre-trial insulin treatment will remain on this dose throughout the study (52 weeks). Administered subcutaneously (s.c., under the skin) once daily.
Placebo Comparator: Liraglutide placebo 0.6 mg + insulin	Drug: placebo; Subjects randomised to 0.6 mg liraglutide treatment or liraglutide placebo as an add-on to their pre-trial insulin treatment will remain on this dose throughout the study (52 weeks). Administered subcutaneously (s.c., under the skin) once daily.
Placebo Comparator: Liraglutide placebo 1.2 mg + insulin	Drug: placebo; Subjects randomised to 0.6 mg liraglutide treatment or liraglutide placebo as an add-on to their pre-trial insulin treatment will remain on this dose throughout the study (52 weeks). Administered subcutaneously (s.c., under the skin) once daily.
Placebo Comparator: Liraglutide placebo 1.8 mg + insulin	Drug: placebo; Subjects randomised to 0.6 mg liraglutide treatment or liraglutide placebo as an add-on to their pre-trial insulin treatment will remain on this dose throughout the study (52 weeks). Administered subcutaneously (s.c., under the skin) once daily.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in HbA1c (Glycosylated Haemoglobin) [Week 0, week 52]

   Change from baseline in HbA1c at week 52. Missing values were handled by using a mixed model for repeated measurements (MMRM).

2. Change From Baseline in Body Weight [Week 0, week 52]

   Change from baseline in body weight at week 52. Missing values were handled by using a MMRM.

3. Change From Baseline in Total Daily Insulin Dose [Week 0, week 52]

   Change from baseline in total daily insulin dose at week 52. Change from baseline was represented in terms of ratio to baseline for insulin dose i.e. Total daily insulin dose at week 52/total daily insulin dose at baseline. Missing values were handled by using a MMRM.

Secondary Outcome Measures

1. Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes [Weeks 0-52]

   This is a confirmatory secondary endpoint. Symptomatic hypoglycaemic episodes were defined as: 1) Severe according to the American Diabetes Association (ADA) classification: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. OR 2) Self-monitoring of plasma glucose value of <3.1 mmol/L, with symptoms consistent with hypoglycaemia. A treatment emergent episode is defined as an episode with onset date (or increase in severity) on or after first day of exposure to randomised treatment and up to last dose + 7 days.

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
• • Type 1 diabetes mellitus for 12 months or longer
• • Basal bolus or CSII (Continuous Subcutaneous Insulin Infusion, insulin pump) treatment for 6 months or longer
• • Stable insulin treatment for the last 3 months prior to Screening, as judged and documented by the investigator
• • HbA1c 7.0-10% (Diabetes Control and Complications Trial (DCCT)), both inclusive, (corresponding to 53-86 mmol/mol (International Federation of Clinical Chemistry (IFCC))
• • Ability and willingness to comply with all protocol procedures e.g. correct handling of trial product, complete trial related questionnaires, diaries, self-monitoring of plasma glucose, self titration of insulin and attend all scheduled visits

Exclusion Criteria:

• • Prior use of glucagon-like peptide-1 (GLP-1) receptor agonist or dipeptidyl peptidase IV (DPP-4) inhibitors
• • Use of any medication, which in the investigator's opinion could interfere with the glycaemic control or affect the subject's safety.Premix insulin is not allowed
• • Known proliferative retinopathy or maculopathy requiring acute treatment
• • Severe neuropathy, in particular autonomic neuropathy, i.e. gastroparesis, as judged by the investigator
• • Uncontrolled/ untreated blood pressure at screening above 160 mmHg for systolic or above 100 mmHg for diastolic
• • History of acute or chronic pancreatitis
• • Screening calcitonin value equal to or above 50 ng/L
• • Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia type 2 (MEN2)
• • Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Little Rock	Arkansas	United States	72205
2	Novo Nordisk Investigational Site	Concord	California	United States	94520
3	Novo Nordisk Investigational Site	Encino	California	United States	91436
4	Novo Nordisk Investigational Site	Escondido	California	United States	92025
5	Novo Nordisk Investigational Site	Huntington Beach	California	United States	92648
6	Novo Nordisk Investigational Site	La Mesa	California	United States	91942
7	Novo Nordisk Investigational Site	Lancaster	California	United States	93534
8	Novo Nordisk Investigational Site	Monterey	California	United States	93940
9	Novo Nordisk Investigational Site	San Mateo	California	United States	94401
10	Novo Nordisk Investigational Site	San Ramon	California	United States	94583
11	Novo Nordisk Investigational Site	Walnut Creek	California	United States	94598
12	Novo Nordisk Investigational Site	Denver	Colorado	United States	80209
13	Novo Nordisk Investigational Site	Ft. Lauderdale	Florida	United States	33312
14	Novo Nordisk Investigational Site	Hialeah	Florida	United States	33012
15	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32258
16	Novo Nordisk Investigational Site	Tampa	Florida	United States	33619
17	Novo Nordisk Investigational Site	Atlanta	Georgia	United States	30308-2253
18	Novo Nordisk Investigational Site	Atlanta	Georgia	United States	30318
19	Novo Nordisk Investigational Site	Marietta	Georgia	United States	30060
20	Novo Nordisk Investigational Site	Roswell	Georgia	United States	30076
21	Novo Nordisk Investigational Site	Savannah	Georgia	United States	31405
22	Novo Nordisk Investigational Site	Idaho Falls	Idaho	United States	83404-7596
23	Novo Nordisk Investigational Site	Indianapolis	Indiana	United States	46254
24	Novo Nordisk Investigational Site	Council Bluffs	Iowa	United States	51501
25	Novo Nordisk Investigational Site	Iowa City	Iowa	United States	52242
26	Novo Nordisk Investigational Site	Topeka	Kansas	United States	66606
27	Novo Nordisk Investigational Site	Metarie	Louisiana	United States	70006
28	Novo Nordisk Investigational Site	Baltimore	Maryland	United States	21229
29	Novo Nordisk Investigational Site	Minneapolis	Minnesota	United States	55416
30	Novo Nordisk Investigational Site	Chesterfield	Missouri	United States	63017
31	Novo Nordisk Investigational Site	Springfield	Missouri	United States	65807
32	Novo Nordisk Investigational Site	St. Charles	Missouri	United States	63303
33	Novo Nordisk Investigational Site	St. Louis	Missouri	United States	63110-1020
34	Novo Nordisk Investigational Site	St. Peters	Missouri	United States	63376
35	Novo Nordisk Investigational Site	Billings	Montana	United States	59101
36	Novo Nordisk Investigational Site	Butte	Montana	United States	59701
37	Novo Nordisk Investigational Site	Lawrenceville	New Jersey	United States	08648
38	Novo Nordisk Investigational Site	Albany	New York	United States	12206
39	Novo Nordisk Investigational Site	Mineola	New York	United States	11501
40	Novo Nordisk Investigational Site	New York	New York	United States	10029
41	Novo Nordisk Investigational Site	New York	New York	United States	10032
42	Novo Nordisk Investigational Site	Staten Island	New York	United States	10301
43	Novo Nordisk Investigational Site	Syracuse	New York	United States	13210
44	Novo Nordisk Investigational Site	Greensboro	North Carolina	United States	27408
45	Novo Nordisk Investigational Site	Morehead City	North Carolina	United States	28557
46	Novo Nordisk Investigational Site	Mentor	Ohio	United States	44060
47	Novo Nordisk Investigational Site	Pittsburgh	Pennsylvania	United States	15224-2215
48	Novo Nordisk Investigational Site	Upper Darby	Pennsylvania	United States	19082
49	Novo Nordisk Investigational Site	Greer	South Carolina	United States	29651
50	Novo Nordisk Investigational Site	Myrtle Beach	South Carolina	United States	29572
51	Novo Nordisk Investigational Site	Summerville	South Carolina	United States	29485
52	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37404-1192
53	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37411
54	Novo Nordisk Investigational Site	Memphis	Tennessee	United States	38119-3821
55	Novo Nordisk Investigational Site	Nashville	Tennessee	United States	37203
56	Novo Nordisk Investigational Site	Nashville	Tennessee	United States	37212
57	Novo Nordisk Investigational Site	Amarillo	Texas	United States	79106
58	Novo Nordisk Investigational Site	Dallas	Texas	United States	75230
59	Novo Nordisk Investigational Site	Dallas	Texas	United States	75231
60	Novo Nordisk Investigational Site	Dallas	Texas	United States	75246
61	Novo Nordisk Investigational Site	El Paso	Texas	United States	79912
62	Novo Nordisk Investigational Site	Round Rock	Texas	United States	78681
63	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77478
64	Novo Nordisk Investigational Site	Salt Lake City	Utah	United States	84102
65	Novo Nordisk Investigational Site	Bennington	Vermont	United States	05201
66	Novo Nordisk Investigational Site	Norfolk	Virginia	United States	23510
67	Novo Nordisk Investigational Site	Federal Way	Washington	United States	98003
68	Novo Nordisk Investigational Site	Spokane	Washington	United States	99208
69	Novo Nordisk Investigational Site	Milwaukee	Wisconsin	United States	53209
70	Novo Nordisk Investigational Site	Milwaukee	Wisconsin	United States	53226
71	Novo Nordisk Investigational Site	Caba		Argentina	C1118AAT
72	Novo Nordisk Investigational Site	Caba		Argentina	C1440AAD
73	Novo Nordisk Investigational Site	Capital Federal		Argentina	1405
74	Novo Nordisk Investigational Site	Córdoba		Argentina	X5016KEH
75	Novo Nordisk Investigational Site	Mendoza		Argentina	5500
76	Novo Nordisk Investigational Site	Morón		Argentina	B1708IFF
77	Novo Nordisk Investigational Site	Broadmeadow	New South Wales	Australia	2292
78	Novo Nordisk Investigational Site	Elizabeth Vale	South Australia	Australia	5112
79	Novo Nordisk Investigational Site	Keswick	South Australia	Australia	5035
80	Novo Nordisk Investigational Site	Melbourne	Victoria	Australia	3004
81	Novo Nordisk Investigational Site	Parkville	Victoria	Australia	3050
82	Novo Nordisk Investigational Site	Arlon		Belgium	6700
83	Novo Nordisk Investigational Site	Edegem		Belgium	2650
84	Novo Nordisk Investigational Site	Leuven		Belgium	3000
85	Novo Nordisk Investigational Site	Liège		Belgium	4000
86	Novo Nordisk Investigational Site	Edmonton	Alberta	Canada	T6G 2E1
87	Novo Nordisk Investigational Site	Winnipeg	Manitoba	Canada	R3E 3P4
88	Novo Nordisk Investigational Site	Barrie	Ontario	Canada	L4M 7G1
89	Novo Nordisk Investigational Site	Cambridge	Ontario	Canada	N1R 7L6
90	Novo Nordisk Investigational Site	London	Ontario	Canada	N6A 4V2
91	Novo Nordisk Investigational Site	Mississauga	Ontario	Canada	L5M 2V8
92	Novo Nordisk Investigational Site	Oakville	Ontario	Canada	L6M 1M1
93	Novo Nordisk Investigational Site	Thornhill	Ontario	Canada	L4J 8L7
94	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M4G 3E8
95	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5C 2T2
96	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5T 3L9
97	Novo Nordisk Investigational Site	Montreal	Quebec	Canada	H2W 1R7
98	Novo Nordisk Investigational Site	Sherbrooke	Quebec	Canada	J1G 5K2
99	Novo Nordisk Investigational Site	Quebec		Canada	G1V 4G2
100	Novo Nordisk Investigational Site	Quebec		Canada	G1V 4G5
101	Novo Nordisk Investigational Site	Helsinki		Finland	00029
102	Novo Nordisk Investigational Site	Helsinki		Finland	00250
103	Novo Nordisk Investigational Site	Pori		Finland	28500
104	Novo Nordisk Investigational Site	Seinäjoki		Finland	60220
105	Novo Nordisk Investigational Site	Seinäjoki		Finland	60510
106	Novo Nordisk Investigational Site	Tampere		Finland	33520
107	Novo Nordisk Investigational Site	Turku		Finland	FI-20520
108	Novo Nordisk Investigational Site	Besancon		France	25030
109	Novo Nordisk Investigational Site	Brest		France	29609
110	Novo Nordisk Investigational Site	Caen		France	14033
111	Novo Nordisk Investigational Site	Corbeil Essonnes		France	91106
112	Novo Nordisk Investigational Site	DIJON cedex		France	21079
113	Novo Nordisk Investigational Site	Le Creusot		France	71200
114	Novo Nordisk Investigational Site	Narbonne		France	11108
115	Novo Nordisk Investigational Site	Paris		France	75877
116	Novo Nordisk Investigational Site	Pointe à Pitre		France	97159
117	Novo Nordisk Investigational Site	Poitiers		France	86000
118	Novo Nordisk Investigational Site	Saint Herblain		France	44800
119	Novo Nordisk Investigational Site	Saint Priest en Jarez		France	42270
120	Novo Nordisk Investigational Site	Venissieux		France	69200
121	Novo Nordisk Investigational Site	Eisenach		Germany	99817
122	Novo Nordisk Investigational Site	Essen		Germany	45219
123	Novo Nordisk Investigational Site	Hamburg		Germany	21073
124	Novo Nordisk Investigational Site	Hamburg		Germany	22607
125	Novo Nordisk Investigational Site	Hohenmölsen		Germany	06679
126	Novo Nordisk Investigational Site	Marburg		Germany	35039
127	Novo Nordisk Investigational Site	Münster		Germany	48145
128	Novo Nordisk Investigational Site	Pohlheim		Germany	35415
129	Novo Nordisk Investigational Site	Rehlingen-Siersburg		Germany	66780
130	Novo Nordisk Investigational Site	St. Ingbert		Germany	66386
131	Novo Nordisk Investigational Site	Dublin 9		Ireland
132	Novo Nordisk Investigational Site	Dublin		Ireland	DUBLIN 15
133	Novo Nordisk Investigational Site	Dublin		Ireland	DUBLIN 4
134	Novo Nordisk Investigational Site	Dublin		Ireland	DUBLIN 7
135	Novo Nordisk Investigational Site	Galway		Ireland
136	Novo Nordisk Investigational Site	Haifa		Israel	31096
137	Novo Nordisk Investigational Site	Holon		Israel	58100
138	Novo Nordisk Investigational Site	Jerusalem		Israel	91120
139	Novo Nordisk Investigational Site	Jerusalem		Israel	93106
140	Novo Nordisk Investigational Site	Petah Tikva		Israel	49202
141	Novo Nordisk Investigational Site	Rishon Le Zion		Israel	75650
142	Novo Nordisk Investigational Site	Amsterdam		Netherlands	1105 AZ
143	Novo Nordisk Investigational Site	Den Haag		Netherlands	2512 VA
144	Novo Nordisk Investigational Site	Hoogeveen		Netherlands	7909 AA
145	Novo Nordisk Investigational Site	Leiden		Netherlands	2333 ZA
146	Novo Nordisk Investigational Site	Nijmegen		Netherlands	6525 GA
147	Novo Nordisk Investigational Site	Rotterdam		Netherlands	3011 TA
148	Novo Nordisk Investigational Site	Venlo		Netherlands	5912 BL
149	Novo Nordisk Investigational Site	Bergen		Norway	5021
150	Novo Nordisk Investigational Site	Gjettum		Norway	1346
151	Novo Nordisk Investigational Site	Hamar		Norway	2318
152	Novo Nordisk Investigational Site	Kongsvinger		Norway	2226
153	Novo Nordisk Investigational Site	Stavanger		Norway	4011
154	Novo Nordisk Investigational Site	Lublin		Poland	20-044
155	Novo Nordisk Investigational Site	Pulawy		Poland	24-100
156	Novo Nordisk Investigational Site	Warszawa		Poland	00-911
157	Novo Nordisk Investigational Site	Warszawa		Poland	03-242
158	Novo Nordisk Investigational Site	Zabrze		Poland	41-800
159	Novo Nordisk Investigational Site	Kazan		Russian Federation	420012
160	Novo Nordisk Investigational Site	Kazan		Russian Federation	420073
161	Novo Nordisk Investigational Site	Penza		Russian Federation	440026
162	Novo Nordisk Investigational Site	Saratov		Russian Federation	410012
163	Novo Nordisk Investigational Site	Volgograd		Russian Federation	400138
164	Novo Nordisk Investigational Site	Göteborg		Sweden	413 45
165	Novo Nordisk Investigational Site	Malmö		Sweden	205 02
166	Novo Nordisk Investigational Site	Stockholm		Sweden	112 81
167	Novo Nordisk Investigational Site	Stockholm		Sweden	141 86
168	Novo Nordisk Investigational Site	Kharkov		Ukraine	61058
169	Novo Nordisk Investigational Site	Kharkov		Ukraine	61070
170	Novo Nordisk Investigational Site	Kiev		Ukraine	04114
171	Novo Nordisk Investigational Site	Poltava		Ukraine	36011
172	Novo Nordisk Investigational Site	Zhytomir		Ukraine	10002
173	Novo Nordisk Investigational Site	Blackburn		United Kingdom	BB2 3HH
174	Novo Nordisk Investigational Site	Bristol		United Kingdom	BS10 5NB
175	Novo Nordisk Investigational Site	Durham		United Kingdom	DH11 5TW
176	Novo Nordisk Investigational Site	Edgbaston, Birmingham		United Kingdom	B15 2TH
177	Novo Nordisk Investigational Site	Edinburgh		United Kingdom	EH4 2XU
178	Novo Nordisk Investigational Site	Middlesbrough		United Kingdom	TS4 3BW
179	Novo Nordisk Investigational Site	Plymouth		United Kingdom	PL6 8BQ
180	Novo Nordisk Investigational Site	Southall		United Kingdom	UB1 3HW
181	Novo Nordisk Investigational Site	St Helens		United Kingdom	WA9 3DA
182	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: NCT01836523
• Other Study ID Numbers: NN9211-3919; 2012-003580-21; U1111-1133-0590
• First Posted: Apr 22, 2013
• Last Update Posted: Mar 6, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Liraglutide

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 177 sites in 17 countries: Argentina: 6, Australia: 5, Belgium: 4, Canada: 14, Germany: 8, Finland: 6, France: 13, United Kingdom: 10, Ireland: 5, Israel: 6, Netherlands: 6, Norway: 5, Poland: 5, Russia: 5, Sweden: 4, Ukraine: 5, United States: 70
Pre-assignment Detail	Eligible subjects were randomised in a 3:3:3:1:1:1 manner to receive liraglutide (0.6 mg, 1.2 mg or 1.8 mg) or placebo (0.1 mL, 0.2 mL or 0.3 mL), both adjunct to insulin treatment.

Arm/Group Title	Liraglutide 0.6 mg	Liraglutide 1.2 mg	Liraglutide 1.8 mg	Placebo
Arm/Group Description	Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Period Title: Overall Study
STARTED	351	350	349	348
Exposed	350	348	347	348
COMPLETED	300	265	258	274
NOT COMPLETED	51	85	91	74

Baseline Characteristics

Arm/Group Title	Liraglutide 0.6 mg	Liraglutide 1.2 mg	Liraglutide 1.8 mg	Placebo	Total
Arm/Group Description	Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.	Total of all reporting groups
Overall Participants	350	346	346	347	1389
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.6 (12.78)	43.9 (13.06)	43.7 (13.33)	43.4 (12.57)	43.7 (12.93)
Gender (Count of Participants)
Female	186 53.1%	179 51.7%	181 52.3%	180 51.9%	726 52.3%
Male	164 46.9%	167 48.3%	165 47.7%	167 48.1%	663 47.7%
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.18 (0.738)	8.16 (0.779)	8.14 (0.740)	8.15 (0.728)	8.16 (0.746)
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	86.54 (17.338)	85.39 (17.210)	86.27 (17.321)	86.41 (17.768)	86.15 (17.397)
Total daily actual insulin dose-continuous subcutaneous insulin infusion (units) [Geometric Mean (Full Range) ]
Geometric Mean (Full Range) [units]	52.97	50.73	50.46	49.18	50.65
Total daily actual insulin dose - Multiple daily injections (units) [Geometric Mean (Full Range) ]
Geometric Mean (Full Range) [units]	59.54	59.61	62.52	62.42	60.94

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Description	Change from baseline in HbA1c at week 52. Missing values were handled by using a mixed model for repeated measurements (MMRM).
Time Frame	Week 0, week 52

Outcome Measure Data

Analysis Population Description

Full analysis set. Number of subjects analysed=subjects with any post-baseline HbA1c data.

Arm/Group Title	Liraglutide 0.6 mg	Liraglutide 1.2 mg	Liraglutide 1.8 mg	Placebo
Arm/Group Description	Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Measure Participants	334	312	305	324
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	-0.45 (0.741)	-0.50 (0.767)	-0.54 (0.729)	-0.34 (0.707)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 1.8 mg, Placebo
	Comments	Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was concluded if the upper bound of 95% confidence interval was <0.3.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.32 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 1.2 mg, Placebo
	Comments	Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was concluded if the upper bound of 95% confidence interval was <0.3.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.27 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 0.6 mg, Placebo
	Comments	Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was concluded if the upper bound of 95% confidence interval was <0.3.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in Body Weight
Description	Change from baseline in body weight at week 52. Missing values were handled by using a MMRM.
Time Frame	Week 0, week 52

Outcome Measure Data

Analysis Population Description

Full analysis set. Number of subjects analysed=subjects with any post-baseline body weight data.

Arm/Group Title	Liraglutide 0.6 mg	Liraglutide 1.2 mg	Liraglutide 1.8 mg	Placebo
Arm/Group Description	Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Measure Participants	324	300	298	311
Mean (Standard Deviation) [kg]	-1.34 (4.183)	-2.73 (4.524)	-4.02 (4.873)	0.94 (3.828)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 1.8 mg, Placebo
	Comments	Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-4.90
	Confidence Interval	(2-Sided) 95%; -5.65 to -4.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 1.2 mg, Placebo
	Comments	Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-3.55
	Confidence Interval	(2-Sided) 95%; -4.29 to -2.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 0.6 mg, Placebo
	Comments	Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-2.19
	Confidence Interval	(2-Sided) 95%; -2.91 to -1.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in Total Daily Insulin Dose
Description	Change from baseline in total daily insulin dose at week 52. Change from baseline was represented in terms of ratio to baseline for insulin dose i.e. Total daily insulin dose at week 52/total daily insulin dose at baseline. Missing values were handled by using a MMRM.
Time Frame	Week 0, week 52

Outcome Measure Data

Analysis Population Description

Full analysis set. Number of subjects analysed=subjects with any post-baseline total insulin daily dose data.

Arm/Group Title	Liraglutide 0.6 mg	Liraglutide 1.2 mg	Liraglutide 1.8 mg	Placebo
Arm/Group Description	Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Measure Participants	337	328	331	341
Geometric Mean (Geometric Coefficient of Variation) [ratio]	1.04 (23.75)	0.98 (26.66)	0.95 (24.21)	1.04 (26.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 1.8 mg, Placebo
	Comments	Analysis was done using MMRMs where all post-baseline measurements for specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as dependent variable, and visit, treatment, country and stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate. The measurements were log-transformed before analysis
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment ratio
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.88 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 1.2 mg, Placebo
	Comments	Analysis was done using MMRMs where all post-baseline measurements for specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as dependent variable, and visit, treatment, country and stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate. The measurements were log-transformed before analysis
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0148
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment ratio
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.91 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 0.6 mg, Placebo
	Comments	Analysis was done using MMRMs where all post-baseline measurements for specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as dependent variable, and visit, treatment, country and stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate. The measurements were log-transformed before analysis
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9615
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment ratio
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.96 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes
Description	This is a confirmatory secondary endpoint. Symptomatic hypoglycaemic episodes were defined as: 1) Severe according to the American Diabetes Association (ADA) classification: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. OR 2) Self-monitoring of plasma glucose value of <3.1 mmol/L, with symptoms consistent with hypoglycaemia. A treatment emergent episode is defined as an episode with onset date (or increase in severity) on or after first day of exposure to randomised treatment and up to last dose + 7 days.
Time Frame	Weeks 0-52

Outcome Measure Data

Analysis Population Description

The safety analysis set included all randomised subjects exposed to at least one dose of liraglutide or placebo.

Arm/Group Title	Liraglutide 0.6 mg	Liraglutide 1.2 mg	Liraglutide 1.8 mg	Placebo
Arm/Group Description	Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Measure Participants	350	348	347	348
Number [episodes]	4954	4602	4614	3654

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 1.8 mg, Placebo
	Comments	The endpoint was analysed using a negative binomial regression model with a log-link function and the log of the time period in which an occurrence of a hypoglycaemic episode was considered treatment emergent as offset. The model included fixed factors (treatment, country, stratification group) and a covariate (baseline HbA1c).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0081
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 1.07 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 1.2 mg, Placebo
	Comments	The endpoint was analysed using a negative binomial regression model with a log-link function and the log of the time period in which an occurrence of a hypoglycaemic episode was considered treatment emergent as offset. The model included fixed factors (treatment, country, stratification group) and a covariate (baseline HbA1c).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0219
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 95%; 1.03 to 1.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 0.6 mg, Placebo
	Comments	The endpoint was analysed using a negative binomial regression model with a log-link function and the log of the time period in which an occurrence of a hypoglycaemic episode was considered treatment emergent as offset. The model included fixed factors (treatment, country, stratification group) and a covariate (baseline HbA1c).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1079
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95%; 0.97 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 52 weeks
Adverse Event Reporting Description	A treatment emergent adverse event is defined as an event with onset date (or increase in severity) on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.
Arm/Group Title	Liraglutide 0.6 mg		Liraglutide 1.2 mg		Liraglutide 1.8 mg		Placebo
Arm/Group Description	Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.		Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.		Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.		Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
All Cause Mortality
	Liraglutide 0.6 mg		Liraglutide 1.2 mg		Liraglutide 1.8 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Liraglutide 0.6 mg		Liraglutide 1.2 mg		Liraglutide 1.8 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/350 (10%)		36/348 (10.3%)		29/347 (8.4%)		38/348 (10.9%)
Cardiac disorders
Acute myocardial infarction	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Angina pectoris	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Atrial fibrillation	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Cardiac arrest	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	1/348 (0.3%)	1
Coronary artery disease	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Myocardial infarction	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Myocarditis	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Congenital, familial and genetic disorders
Melkersson-Rosenthal syndrome	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Ear and labyrinth disorders
Vertigo	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Vertigo positional	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Eye disorders
Glaucoma	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Macular oedema	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Retinopathy	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Gastrointestinal disorders
Dyspepsia	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Dysphagia	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Large intestine polyp	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Nausea	1/350 (0.3%)	1	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Pancreatitis	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Rectal prolapse	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Vomiting	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
General disorders
Chest pain	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Cyst	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Malaise	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Hepatobiliary disorders
Cholecystitis	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Cholecystitis acute	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Cholelithiasis	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Immune system disorders
Anaphylactic reaction	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Infections and infestations
Abscess	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Abscess limb	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Appendicitis	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	2/348 (0.6%)	2
Arthritis bacterial	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Arthritis infective	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Cellulitis	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Erysipelas	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Gastroenteritis	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Herpes zoster	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Incision site infection	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Infectious mononucleosis	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Lower respiratory tract infection	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Otitis externa	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Pharyngitis streptococcal	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	1/348 (0.3%)	1
Pilonidal cyst	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Pneumonia	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Sepsis	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Subcutaneous abscess	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Upper respiratory tract infection	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Urinary tract infection	0/350 (0%)	0	0/348 (0%)	0	3/347 (0.9%)	3	0/348 (0%)	0
Wound infection	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Injury, poisoning and procedural complications
Accidental overdose	1/350 (0.3%)	1	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Ankle fracture	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Craniocerebral injury	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Fall	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Foot fracture	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Ligament rupture	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Post procedural haemorrhage	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Suture related complication	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Tibia fracture	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Investigations
Biopsy prostate	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Diabetic ketoacidosis	3/350 (0.9%)	3	1/348 (0.3%)	1	3/347 (0.9%)	3	0/348 (0%)	0
Hyperglycaemia	3/350 (0.9%)	5	3/348 (0.9%)	4	3/347 (0.9%)	4	2/348 (0.6%)	2
Hyperkalaemia	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Hyperosmolar hyperglycaemic state	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Hypoglycaemia	3/350 (0.9%)	4	7/348 (2%)	8	5/347 (1.4%)	5	13/348 (3.7%)	16
Hyponatraemia	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Bursitis	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Dupuytren's contracture	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Intervertebral disc protrusion	0/350 (0%)	0	1/348 (0.3%)	1	1/347 (0.3%)	1	0/348 (0%)	0
Joint effusion	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Musculoskeletal pain	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Osteoarthritis	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Spinal column stenosis	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Haemangioma of bone	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Invasive lobular breast carcinoma	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Malignant melanoma	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	1/348 (0.3%)	1
Papillary thyroid cancer	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Nervous system disorders
Cerebrospinal fluid leakage	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Hypoglycaemic seizure	1/350 (0.3%)	1	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Hypoglycaemic unconsciousness	5/350 (1.4%)	5	3/348 (0.9%)	3	6/347 (1.7%)	7	6/348 (1.7%)	7
Migraine	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Transient ischaemic attack	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Psychiatric disorders
Alcoholism	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Completed suicide	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Depression	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Depression suicidal	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Panic attack	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Suicide attempt	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Renal and urinary disorders
Acute kidney injury	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Bladder prolapse	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Nephrolithiasis	0/350 (0%)	0	1/348 (0.3%)	1	0/347 (0%)	0	0/348 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	0/350 (0%)	0	0/348 (0%)	0	1/347 (0.3%)	1	0/348 (0%)	0
Dyspnoea	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Tonsillar inflammation	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Skin and subcutaneous tissue disorders
Diabetic foot	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Urticaria	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Surgical and medical procedures
Obesity surgery	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Toe amputation	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Vascular disorders
Hypertensive crisis	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	0/348 (0%)	0
Peripheral vascular disorder	1/350 (0.3%)	1	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Popliteal artery entrapment syndrome	0/350 (0%)	0	0/348 (0%)	0	0/347 (0%)	0	1/348 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Liraglutide 0.6 mg		Liraglutide 1.2 mg		Liraglutide 1.8 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	259/350 (74%)		263/348 (75.6%)		282/347 (81.3%)		224/348 (64.4%)
Gastrointestinal disorders
Abdominal pain	20/350 (5.7%)	32	16/348 (4.6%)	20	29/347 (8.4%)	41	8/348 (2.3%)	9
Constipation	17/350 (4.9%)	20	28/348 (8%)	30	26/347 (7.5%)	28	9/348 (2.6%)	11
Diarrhoea	41/350 (11.7%)	52	50/348 (14.4%)	69	64/347 (18.4%)	92	38/348 (10.9%)	50
Dyspepsia	26/350 (7.4%)	37	27/348 (7.8%)	41	38/347 (11%)	48	8/348 (2.3%)	8
Nausea	112/350 (32%)	146	141/348 (40.5%)	196	172/347 (49.6%)	271	42/348 (12.1%)	52
Vomiting	24/350 (6.9%)	26	44/348 (12.6%)	58	64/347 (18.4%)	106	21/348 (6%)	26
General disorders
Fatigue	17/350 (4.9%)	18	22/348 (6.3%)	24	18/347 (5.2%)	21	16/348 (4.6%)	18
Infections and infestations
Gastroenteritis	21/350 (6%)	25	15/348 (4.3%)	17	29/347 (8.4%)	32	15/348 (4.3%)	21
Gastroenteritis viral	12/350 (3.4%)	14	6/348 (1.7%)	6	18/347 (5.2%)	24	8/348 (2.3%)	10
Influenza	29/350 (8.3%)	32	17/348 (4.9%)	26	25/347 (7.2%)	28	24/348 (6.9%)	30
Nasopharyngitis	105/350 (30%)	175	81/348 (23.3%)	124	83/347 (23.9%)	145	85/348 (24.4%)	130
Sinusitis	24/350 (6.9%)	35	17/348 (4.9%)	22	16/347 (4.6%)	21	21/348 (6%)	31
Upper respiratory tract infection	33/350 (9.4%)	37	23/348 (6.6%)	37	43/347 (12.4%)	59	40/348 (11.5%)	58
Urinary tract infection	18/350 (5.1%)	28	14/348 (4%)	21	20/347 (5.8%)	26	11/348 (3.2%)	15
Metabolism and nutrition disorders
Decreased appetite	31/350 (8.9%)	32	43/348 (12.4%)	45	64/347 (18.4%)	70	6/348 (1.7%)	6
Hyperglycaemia	17/350 (4.9%)	29	17/348 (4.9%)	26	22/347 (6.3%)	38	17/348 (4.9%)	28
Hypoglycaemia	26/350 (7.4%)	32	13/348 (3.7%)	18	20/347 (5.8%)	37	24/348 (6.9%)	35
Musculoskeletal and connective tissue disorders
Back pain	15/350 (4.3%)	17	22/348 (6.3%)	24	18/347 (5.2%)	19	16/348 (4.6%)	16
Nervous system disorders
Headache	56/350 (16%)	78	46/348 (13.2%)	85	49/347 (14.1%)	119	40/348 (11.5%)	77
Respiratory, thoracic and mediastinal disorders
Cough	14/350 (4%)	14	7/348 (2%)	8	10/347 (2.9%)	12	21/348 (6%)	24
Oropharyngeal pain	15/350 (4.3%)	17	22/348 (6.3%)	24	28/347 (8.1%)	32	13/348 (3.7%)	15

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Novo Nordisk commits to communicating, and otherwise making available for public disclosure, results of trials regardless of outcome.At the end of the trial, one or more public disclosures may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.