DUAL™ III: The Efficacy of Insulin Degludec/Liraglutide in Controlling Glycaemia in Adults With Type 2 Diabetes Inadequately Controlled on GLP-1 Receptor Agonist and OAD Therapy

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01676116
• Collaborator: (none)
• Enrollment: 438
• Locations: 109
• Arms: 2
• Actual Duration (Months): 18.4
• Patients Per Site: 4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This trial is conducted in Europe, Oceania and the United States of America (USA).

The aim of the trial is to investigate the efficacy of insulin degludec/liraglutide in controlling glycaemia in adults with type 2 diabetes inadequately controlled on glucagon-like peptide-1 (GLP-1) receptor agonist and OAD therapy.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 438 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Efficacy of Insulin Degludec/Liraglutide in Controlling Glycaemia in Adults With Type 2 Diabetes Inadequately Controlled on GLP-1 Receptor Agonist and OAD Therapy (DUAL™ III -GLP-1 Switch)
• Actual Study Start Date: Aug 29, 2012
• Actual Primary Completion Date: Mar 11, 2014
• Actual Study Completion Date: Mar 11, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Insulin degludec/liraglutide + OADs	Drug: insulin degludec/liraglutide; Injected subcutaneously (under the skin) once daily. Dose individually adjusted. Subjects will continue their pre-trial OAD treatment without changing the frequency or dose throughout the trial.
Active Comparator: Liraglutide or exenatide + OADs	Drug: liraglutide; Subjects will continue on their pre-trial treatment of liraglutide (Victoza®) (GLP-1 receptor agonist) + OAD without changing the frequency or dose throughout the trial.; Drug: exenatide; Subjects will continue on their pre-trial treatment of exenatide (Byetta®) (GLP-1 receptor agonist) + OAD without changing the frequency or dose throughout the trial.

Outcome Measures

Primary Outcome Measures

1. Change in Glycosylated Haemoglobin (HbA1c) From Baseline (Randomisation, Visit 2) [Week 0, week 26]

Secondary Outcome Measures

1. Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol) [Week 26]

   Percentage of subjects achieving HbA1c below 7.0% after 26 weeks of treatment.

2. Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol) [Week 26]

   Percentage of responders achieving pre-defined target for HbA1c - HbA1c ≤ 6.5% (48 mmol/mol).

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

   Mean change in body weight after 26 weeks of treatment.

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

   Mean change in fasting plasma glucose from baseline, after 26 weeks of treatment.

5. Number of Severe or Minor Hypoglycaemic Episodes [After 26 weeks of treatment]

   Rate (events per 100 patient years of exposure) of treatment-emergent confirmed hypoglycaemic episodes. The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes. Severe hypoglycaemia was categorised as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose <2.8 mmol/L (50 mg/dL) or PG <3.1 mmol/L (56 mg/dL), and which was handled by the subject himself/herself, or any asymptomatic blood glucose value <2.8 mmol/L (50 mg/dL) or PG value <3.1 mmol/L (56 mg/dL).

6. Number of Adverse Events (AEs) [After 26 weeks of treatment]

   Rate (events per 100 exposure years) of treatment-emergent adverse events (an event that had onset date (or an 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) which occurred during the 26 weeks of treatment.

7. Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) [Week 0, week 26]

   The patient related outcome is calculated based on TRIM-D questionnaire. The TRIM-D questionnaire consists of 5 sub-domains (treatment burden, daily life, diabetes management, compliance and psychological health), where each question is scored to a 1-5-point scale with a higher score indicating a better health state (less negative impact). Mean TRIM-D individual sub-domain scores and total score are later transformed to a 0-100 scale for analysis. The mean change in scores from baseline to 26 weeks for all the individual sub domains and total scores are presented here.

8. Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ). [Week 0, week 26]

   Mean change in diabetes treatment satisfaction questionnaire (DTSQs) scores from baseline. The scores ranged from 0 to 6. Higher total score on a 0-6 point scale indicates a general higher treatment satisfaction, whereas higher score on perceived frequency of hyperglycaemia and perceived frequency of hypoglycaemia indicate that blood glucose levels are out of the target range.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects with type 2 diabetes mellitus

• Glycosylated haemoglobin (HbA1c) 7.0-9.0% (53-75 mmol/mol) (both inclusive)

• Treatment with daily GLP-1 receptor agonist at maximum dose according to local label (i.e. 1.8 mg once daily (OD) Victoza® (liraglutide) or 10 microgram twice daily (BID) Byetta® (exenatide)) or documented maximum tolerated dose (i.e. 1.2 mg OD Victoza® (liraglutide) or 5 microgram BID Byetta® (exenatide)) in combination with a stable daily dose of metformin (equal to or above 1500 mg or documented maximum tolerated dose) for 90 days or more prior to screening visit (Visit 1)

• BMI (body mass index) equal to or below 40 kg/m^2

Exclusion Criteria:

• Any use of oral anti-diabetic drugs (OADs) (except for metformin, pioglitazone and sulphonylurea) for 90 days or less prior to screening visit (Visit 1)

• Use of any drug (except metformin,pioglitazone, sulphonylurea and GLP-1 receptor agonist) which in the Investigator's opinion could interfere with the blood glucose level (e.g. systemic corticosteroids)

• Treatment with any insulin regimen (short term treatment due to intercurrent illness including gestational diabetes is allowed at the discretion of the Investigator)

• Screening calcitonin equal to or above 50 ng/l

• Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2)

• Cardiovascular disorders defined as: congestive heart failure (New York Heart Association (NYHA) class III-IV), diagnosis of unstable angina pectoris, cerebral stroke and/or myocardial infarction within the past 52 weeks prior to screening visit (Visit 1) and/or planned coronary, carotid or peripheral artery revascularisation procedures

• Proliferative retinopathy requiring acute treatment or maculopathy (macular oedema) according to the Investigator's opinion

• Subjects with a clinically significant, active (during the past 12 months) disease of the gastrointestinal, pulmonary, endocrinological (except for the type 2 diabetes mellitus), neurological, genitourinary or haematological system that in the opinion of the Investigator may confound the results of the trial or pose additional risk in administering trial products

• History of chronic pancreatitis or idiopathic acute pancreatitis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Birmingham	Alabama	United States	35216
2	Novo Nordisk Investigational Site	Goodyear	Arizona	United States	85395
3	Novo Nordisk Investigational Site	Mesa	Arizona	United States	85206
4	Novo Nordisk Investigational Site	Phoenix	Arizona	United States	85018
5	Novo Nordisk Investigational Site	Concord	California	United States	94520
6	Novo Nordisk Investigational Site	Encino	California	United States	91436
7	Novo Nordisk Investigational Site	Fair Oaks	California	United States	95628
8	Novo Nordisk Investigational Site	Fresno	California	United States	93720
9	Novo Nordisk Investigational Site	Greenbrae	California	United States	94904
10	Novo Nordisk Investigational Site	Lancaster	California	United States	93534
11	Novo Nordisk Investigational Site	Lomita	California	United States	90717
12	Novo Nordisk Investigational Site	Long Beach	California	United States	90806
13	Novo Nordisk Investigational Site	Montclair	California	United States	91763
14	Novo Nordisk Investigational Site	Northridge	California	United States	91325
15	Novo Nordisk Investigational Site	San Mateo	California	United States	94401
16	Novo Nordisk Investigational Site	San Ramon	California	United States	94583
17	Novo Nordisk Investigational Site	Tarzana	California	United States	91356-3551
18	Novo Nordisk Investigational Site	Van Nuys	California	United States	91405
19	Novo Nordisk Investigational Site	Colorado Springs	Colorado	United States	80910
20	Novo Nordisk Investigational Site	Bradenton	Florida	United States	34201
21	Novo Nordisk Investigational Site	Fort Myers	Florida	United States	33912-4343
22	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32204
23	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32207
24	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32216
25	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32258
26	Novo Nordisk Investigational Site	Miami Springs	Florida	United States	33166
27	Novo Nordisk Investigational Site	Miami	Florida	United States	33135
28	Novo Nordisk Investigational Site	Miami	Florida	United States	33136
29	Novo Nordisk Investigational Site	Miami	Florida	United States	33155
30	Novo Nordisk Investigational Site	Miami	Florida	United States	33156
31	Novo Nordisk Investigational Site	Orlando	Florida	United States	32806
32	Novo Nordisk Investigational Site	Plant City	Florida	United States	33563
33	Novo Nordisk Investigational Site	Winter Haven	Florida	United States	33880
34	Novo Nordisk Investigational Site	Atlanta	Georgia	United States	30318
35	Novo Nordisk Investigational Site	Roswell	Georgia	United States	30076
36	Novo Nordisk Investigational Site	Honolulu	Hawaii	United States	96814
37	Novo Nordisk Investigational Site	Arlington Heights	Illinois	United States	60004-2315
38	Novo Nordisk Investigational Site	Indianapolis	Indiana	United States	46254
39	Novo Nordisk Investigational Site	Lexington	Kentucky	United States	40503
40	Novo Nordisk Investigational Site	Rockville	Maryland	United States	20852
41	Novo Nordisk Investigational Site	Kalamazoo	Michigan	United States	49048
42	Novo Nordisk Investigational Site	Troy	Michigan	United States	48098
43	Novo Nordisk Investigational Site	Saint Charles	Missouri	United States	63303
44	Novo Nordisk Investigational Site	Omaha	Nebraska	United States	68124
45	Novo Nordisk Investigational Site	Henderson	Nevada	United States	89052-2649
46	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89128
47	Novo Nordisk Investigational Site	Reno	Nevada	United States	89502-0111
48	Novo Nordisk Investigational Site	Nashua	New Hampshire	United States	03063
49	Novo Nordisk Investigational Site	Berlin	New Jersey	United States	08009
50	Novo Nordisk Investigational Site	Flemington	New Jersey	United States	08822-5763
51	Novo Nordisk Investigational Site	Hamilton	New Jersey	United States	08619
52	Novo Nordisk Investigational Site	Lawrenceville	New Jersey	United States	08648
53	Novo Nordisk Investigational Site	Toms River	New Jersey	United States	08753-2975
54	Novo Nordisk Investigational Site	Mineola	New York	United States	11501
55	Novo Nordisk Investigational Site	North Massapequa	New York	United States	11758-1802
56	Novo Nordisk Investigational Site	West Seneca	New York	United States	14224
57	Novo Nordisk Investigational Site	Morehead City	North Carolina	United States	28557
58	Novo Nordisk Investigational Site	Columbus	Ohio	United States	43214
59	Novo Nordisk Investigational Site	Dayton	Ohio	United States	45439
60	Novo Nordisk Investigational Site	Altoona	Pennsylvania	United States	16602
61	Novo Nordisk Investigational Site	Pittsburgh	Pennsylvania	United States	15243
62	Novo Nordisk Investigational Site	Myrtle Beach	South Carolina	United States	29572
63	Novo Nordisk Investigational Site	Sumter	South Carolina	United States	29150-1900
64	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37404
65	Novo Nordisk Investigational Site	Jellico	Tennessee	United States	37762
66	Novo Nordisk Investigational Site	Kingsport	Tennessee	United States	37660
67	Novo Nordisk Investigational Site	Nashville	Tennessee	United States	37212
68	Novo Nordisk Investigational Site	Tullahoma	Tennessee	United States	37388
69	Novo Nordisk Investigational Site	Arlington	Texas	United States	76014
70	Novo Nordisk Investigational Site	Austin	Texas	United States	78731
71	Novo Nordisk Investigational Site	Dallas	Texas	United States	75218
72	Novo Nordisk Investigational Site	Dallas	Texas	United States	75231
73	Novo Nordisk Investigational Site	Fort Worth	Texas	United States	76113
74	Novo Nordisk Investigational Site	Houston	Texas	United States	77074
75	Novo Nordisk Investigational Site	Houston	Texas	United States	77095
76	Novo Nordisk Investigational Site	Plano	Texas	United States	75075
77	Novo Nordisk Investigational Site	Round Rock	Texas	United States	78681
78	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78215
79	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78249
80	Novo Nordisk Investigational Site	Schertz	Texas	United States	78154
81	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77478
82	Novo Nordisk Investigational Site	Orem	Utah	United States	84058
83	Novo Nordisk Investigational Site	Saint George	Utah	United States	84790
84	Novo Nordisk Investigational Site	Salt Lake City	Utah	United States	84107
85	Novo Nordisk Investigational Site	Richmond	Virginia	United States	23219
86	Novo Nordisk Investigational Site	Coffs Harbour	New South Wales	Australia	2450
87	Novo Nordisk Investigational Site	Merewether	New South Wales	Australia	2291
88	Novo Nordisk Investigational Site	Keswick	South Australia	Australia	5035
89	Novo Nordisk Investigational Site	Box Hill	Victoria	Australia	3128
90	Novo Nordisk Investigational Site	Melbourne	Victoria	Australia	3004
91	Novo Nordisk Investigational Site	Antibes		France	06600
92	Novo Nordisk Investigational Site	Boulogne Billancourt		France	92100
93	Novo Nordisk Investigational Site	LA ROCHELLE cedex		France	17019
94	Novo Nordisk Investigational Site	Montigny-les-Metz		France	57950
95	Novo Nordisk Investigational Site	Narbonne		France	11108
96	Novo Nordisk Investigational Site	Nimes		France	30006
97	Novo Nordisk Investigational Site	Sète		France	34200
98	Novo Nordisk Investigational Site	Venissieux		France	69200
99	Novo Nordisk Investigational Site	Budapest		Hungary	1042
100	Novo Nordisk Investigational Site	Debrecen		Hungary	4043
101	Novo Nordisk Investigational Site	Nyíregyhaza		Hungary	4400
102	Novo Nordisk Investigational Site	Székesfehérvár		Hungary	8000
103	Novo Nordisk Investigational Site	Bratislava		Slovakia	811 08
104	Novo Nordisk Investigational Site	Bratislava		Slovakia	831 01
105	Novo Nordisk Investigational Site	Bratislava		Slovakia	851 01
106	Novo Nordisk Investigational Site	Kosice		Slovakia	040 01
107	Novo Nordisk Investigational Site	Lucenec		Slovakia	98401
108	Novo Nordisk Investigational Site	Nitra		Slovakia	94 911
109	Novo Nordisk Investigational Site	Presov		Slovakia	080 01

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: NCT01676116
• Other Study ID Numbers: NN9068-3851; 2012-000209-63; U1111-1127-1321
• First Posted: Aug 30, 2012
• Last Update Posted: Jan 3, 2019
• Last Verified: Dec 1, 2018

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 81 sites in 5 countries as follows: Australia: 5 sites; France: 7 sites; Hungary: 4 sites; Slovakia 6 sites; United States: 59 sites.
Pre-assignment Detail	The duration of the screening period was 2 weeks. All subjects continued GLP-1 receptor agonist and metformin±pioglitazone±SU treatments in their pre-trial doses during the screening period.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Period Title: Overall Study
STARTED	292	146
COMPLETED	276	117
NOT COMPLETED	16	29

Baseline Characteristics

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs	Total
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.	Total of all reporting groups
Overall Participants	292	146	438
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.3 (9.9)	58.4 (8.8)	58.3 (9.5)
Sex: Female, Male (Count of Participants)
Female	139 47.6%	75 51.4%	214 48.9%
Male	153 52.4%	71 48.6%	224 51.1%
HbA1c (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	7.8 (0.6)	7.7 (0.6)	7.8 (0.6)
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	95.6 (16.6)	95.5 (17.3)	95.5 (16.8)
Fasting plasma glucose (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	9 (2.1)	9.4 (2.3)	9.1 (2.2)

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c) From Baseline (Randomisation, Visit 2)
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all the randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Measure Participants	292	146
Least Squares Mean (Standard Error) [percentage of glycosylated haemoglobin]	-1.32 (0.05)	-0.37 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs), Liraglutide or Exenatide + OADs
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment contrast
	Estimated Value	-0.94
	Confidence Interval	(2-Sided) 95%; -1.11 to -0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol)
Description	Percentage of subjects achieving HbA1c below 7.0% after 26 weeks of treatment.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Measure Participants	292	146
Number [Percentage]	75.3	35.6

3. Secondary Outcome

Title	Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol)
Description	Percentage of responders achieving pre-defined target for HbA1c - HbA1c ≤ 6.5% (48 mmol/mol).
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Measure Participants	292	146
Number [Percentage]	63	22.6

4. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Mean change in body weight after 26 weeks of treatment.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Measure Participants	292	146
Mean (Standard Deviation) [kg]	2 (3.9)	-0.8 (3.0)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects. A total of 430 subjects contributed to the analysis. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Measure Participants	285	145
Mean (Standard Deviation) [mmol/L]	-2.98 (2.28)	-0.6 (2.74)

6. Secondary Outcome

Title	Number of Severe or Minor Hypoglycaemic Episodes
Description	Rate (events per 100 patient years of exposure) of treatment-emergent confirmed hypoglycaemic episodes. The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes. Severe hypoglycaemia was categorised as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose <2.8 mmol/L (50 mg/dL) or PG <3.1 mmol/L (56 mg/dL), and which was handled by the subject himself/herself, or any asymptomatic blood glucose value <2.8 mmol/L (50 mg/dL) or PG value <3.1 mmol/L (56 mg/dL).
Time Frame	After 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects. A total of 436 subjects contributed to the analysis.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Measure Participants	291	145
Number [events per 100 patient years of exposure]	281.7	12.1

7. Secondary Outcome

Title	Number of Adverse Events (AEs)
Description	Rate (events per 100 exposure years) of treatment-emergent adverse events (an event that had onset date (or an 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) which occurred during the 26 weeks of treatment.
Time Frame	After 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects. A total of 436 subjects contributed to the analysis.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Measure Participants	291	145
Number [events per 100 exposure years]	410.1	364.3

8. Secondary Outcome

Title	Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D)
Description	The patient related outcome is calculated based on TRIM-D questionnaire. The TRIM-D questionnaire consists of 5 sub-domains (treatment burden, daily life, diabetes management, compliance and psychological health), where each question is scored to a 1-5-point scale with a higher score indicating a better health state (less negative impact). Mean TRIM-D individual sub-domain scores and total score are later transformed to a 0-100 scale for analysis. The mean change in scores from baseline to 26 weeks for all the individual sub domains and total scores are presented here.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects. A total of 436 subjects contributed to the analysis. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Measure Participants	290	146
TRIM-D Treatment Burden Score	10.8 (18.8)	5.7 (19.3)
TRIM-D Daily Life Score	6.3 (18.4)	0.8 (18.2)
TRIM-D Diabetes Management Score	10.9 (21.3)	4.1 (19.8)
TRIM-D Compliance Score	8.9 (17.3)	4.3 (15.9)
TRIM-D Psychological Health Score	7.3 (14.7)	1.4 (16.5)
TRIM-D Total Score	8.7 (12)	3.1 (12.2)

9. Secondary Outcome

Title	Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ).
Description	Mean change in diabetes treatment satisfaction questionnaire (DTSQs) scores from baseline. The scores ranged from 0 to 6. Higher total score on a 0-6 point scale indicates a general higher treatment satisfaction, whereas higher score on perceived frequency of hyperglycaemia and perceived frequency of hypoglycaemia indicate that blood glucose levels are out of the target range.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects. A total of 436 subjects contributed to the analysis. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs)	Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.	Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
Measure Participants	290	146
Treatment satisfaction scale total	3.1 (5.6)	1.1 (5.0)
Hyperglycaemia	-1.8 (2.1)	-0.6 (1.9)
Hypoglycaemia	0.2 (1.7)	-0.1 (1.5)

Adverse Events

Time Frame	Adverse events from the first trial-related activity after the subject had signed the informed consent until the end of the post-treatment follow-up period (week 27) are reported.
Adverse Event Reporting Description	Safety analysis set included a total of 436 subjects; (291 in the Insulin degludec/liraglutide+OADs arm and 145 in the Liraglutide or exenatide+OADs arm).
Arm/Group Title	Insulin Degludec/Liraglutide +OADs		Liraglutide or Exenatide + OADs
Arm/Group Description	Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Insulin degludec/liraglutide was dosed on an individual basis. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.		Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
All Cause Mortality
	Insulin Degludec/Liraglutide +OADs		Liraglutide or Exenatide + OADs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Insulin Degludec/Liraglutide +OADs		Liraglutide or Exenatide + OADs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/291 (3.1%)		3/145 (2.1%)
Cardiac disorders
Atrial fibrillation	1/291 (0.3%)	1	0/145 (0%)	0
Endocrine disorders
Adrenal insufficiency	1/291 (0.3%)	1	0/145 (0%)	0
General disorders
Non-cardiac chest pain	1/291 (0.3%)	1	0/145 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	1/291 (0.3%)	1	0/145 (0%)	0
Cholelithiasis	0/291 (0%)	0	1/145 (0.7%)	1
Injury, poisoning and procedural complications
Foot fracture	0/291 (0%)	0	1/145 (0.7%)	1
Road traffic accident	1/291 (0.3%)	1	0/145 (0%)	0
Musculoskeletal and connective tissue disorders
Spinal pain	1/291 (0.3%)	1	0/145 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pituitary tumour	1/291 (0.3%)	1	0/145 (0%)	0
Nervous system disorders
Lacunar infarction	1/291 (0.3%)	1	0/145 (0%)	0
Sciatica	0/291 (0%)	0	1/145 (0.7%)	1
Transient ischaemic attack	1/291 (0.3%)	1	0/145 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/291 (0.3%)	1	0/145 (0%)	0
Surgical and medical procedures
Thrombectomy	1/291 (0.3%)	1	0/145 (0%)	0
Vascular disorders
Peripheral artery thrombosis	1/291 (0.3%)	1	0/145 (0%)	0
Other (Not Including Serious) Adverse Events
	Insulin Degludec/Liraglutide +OADs		Liraglutide or Exenatide + OADs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	88/291 (30.2%)		39/145 (26.9%)
Gastrointestinal disorders
Diarrhoea	13/291 (4.5%)	18	8/145 (5.5%)	9
Infections and infestations
Nasopharyngitis	26/291 (8.9%)	31	19/145 (13.1%)	20
Upper respiratory tract infection	18/291 (6.2%)	18	8/145 (5.5%)	9
Investigations
Lipase increased	29/291 (10%)	31	7/145 (4.8%)	8
Nervous system disorders
Headache	27/291 (9.3%)	31	9/145 (6.2%)	14

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.