DUAL™ VI: A Clinical Trial Comparing Efficacy and Safety of Insulin Degludec/Liraglutide (IDegLira) in Subjects With Type 2 Diabetes Mellitus Using Two Different Titration Algorithms

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02298192
• Collaborator: (none)
• Enrollment: 420
• Locations: 84
• Arms: 2
• Actual Duration (Months): 13
• Patients Per Site: 5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This trial is conducted in Europe, North America and the United States of America.

The aim of this trial is to compare two different titration algorithms of insulin degludec/liraglutide.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 420 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Clinical Trial Comparing Efficacy and Safety of Insulin Degludec/Liraglutide (IDegLira) in Subjects With Type 2 Diabetes Mellitus Using Two Different Titration Algorithms
• Actual Study Start Date: Nov 21, 2014
• Actual Primary Completion Date: Dec 23, 2015
• Actual Study Completion Date: Dec 23, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Once weekly titration	Drug: insulin degludec/liraglutide; For subcutaneous (s.c., under the skin) injection, once daily. Subjects will be instructed to continue with the same dose of OADs (metformin alone or in combination with pioglitazone), as prior to the trial.
Experimental: Twice weekly titration	Drug: insulin degludec/liraglutide; For subcutaneous (s.c., under the skin) injection, once daily. Subjects will be instructed to continue with the same dose of OADs (metformin alone or in combination with pioglitazone), as prior to the trial.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in HbA1c [Week 0, week 32]

   Change in glycosylated haemoglobin A1c (HbA1c) (%) from baseline after 32 weeks of treatment.

Secondary Outcome Measures

1. HbA1c Below 7.0% [Week 0, week 32]

   Responders to HbA1c below 7% after 32 weeks of treatment.

2. HbA1c Below or Equal to 6.5% [Week 0, week 32]

   Responders to HbA1c below or equal to 6.5% after 32 weeks of treatment.

3. Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes [Week 0-32]

   An episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Type 2 diabetes mellitus

• Male or female equal to or above 18 years of age

• HbA1c (glycosylated haemoglobin) 7.0 - 10.0% [53 mmol/mol - 86 mmol/mol] (both inclusive), confirmed by the central laboratory

• Stable daily treatment with metformin (above or equal to 1500 mg or max tolerated dose) with or without pioglitazone (above orequal to 30 mg) for at least 90 days prior to screening

• Body Mass Index (BMI) below or equal to 40 kg/m^2

Exclusion Criteria:

• Current use of any anti-diabetic drugs (except for metformin and pioglitazone) or anticipated change in concomitant medication, which, in the opinion of the investigator, could interfere with the glucose metabolism (e.g. systemic corticosteroids)

• Previous and / or current treatment with insulin (short term treatment due to intercurrent illness, including gestational diabetes, is allowed at the discretion of the investigator)

• Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists, sulpfonylurea, glinides, dipeptidyl peptidase 4 (DPP-4) inhibitors or sodium-glucose co-transporter 2 (SGLT2) inhibitors within 90 days prior to the screening visit

• Impaired liver function, defined as alanine aminotransferase (ALAT) above or equal to 2.5 times upper normal range (UNR)

• Impaired renal function defined as serum-creatinine above or equal to 133 micromol/L (above or equal to 1.5 mg/dL) for males and above or equal to 125 micromol/L (above or equal to 1.4 mg/dL) for females, or as defined according to local contraindications for metformin

• Screening calcitonin above or equal to 50 ng/L

• Proliferative retinopathy or maculopathy (macular oedema) requiring acute treatment, according to investigator's clinical judgment

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

• History of pancreatitis (acute or chronic)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Hamilton	Alabama	United States	35570
2	Novo Nordisk Investigational Site	Chandler	Arizona	United States	85224
3	Novo Nordisk Investigational Site	Glendale	Arizona	United States	85306-4652
4	Novo Nordisk Investigational Site	Glendale	Arizona	United States	85308
5	Novo Nordisk Investigational Site	Mesa	Arizona	United States	85213
6	Novo Nordisk Investigational Site	Phoenix	Arizona	United States	85018
7	Novo Nordisk Investigational Site	Phoenix	Arizona	United States	85020
8	Novo Nordisk Investigational Site	Tucson	Arizona	United States	85741
9	Novo Nordisk Investigational Site	Anaheim	California	United States	92801
10	Novo Nordisk Investigational Site	Palm Springs	California	United States	92262
11	Novo Nordisk Investigational Site	Walnut Creek	California	United States	94598
12	Novo Nordisk Investigational Site	Colorado Springs	Colorado	United States	80904
13	Novo Nordisk Investigational Site	Boynton Beach	Florida	United States	33472
14	Novo Nordisk Investigational Site	Clearwater	Florida	United States	33765
15	Novo Nordisk Investigational Site	Hallandale Beach	Florida	United States	33009
16	Novo Nordisk Investigational Site	Miami	Florida	United States	33173
17	Novo Nordisk Investigational Site	Orlando	Florida	United States	32801
18	Novo Nordisk Investigational Site	Tampa	Florida	United States	33603
19	Novo Nordisk Investigational Site	Conyers	Georgia	United States	30094-5965
20	Novo Nordisk Investigational Site	Blackfoot	Idaho	United States	83221
21	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60607
22	Novo Nordisk Investigational Site	Indianapolis	Indiana	United States	46254
23	Novo Nordisk Investigational Site	Crestview Hills	Kentucky	United States	41017-3464
24	Novo Nordisk Investigational Site	Troy	Michigan	United States	48098
25	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89103
26	Novo Nordisk Investigational Site	Nashua	New Hampshire	United States	03063
27	Novo Nordisk Investigational Site	West Seneca	New York	United States	14224
28	Novo Nordisk Investigational Site	Greensboro	North Carolina	United States	27408
29	Novo Nordisk Investigational Site	Norman	Oklahoma	United States	73069
30	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19107
31	Novo Nordisk Investigational Site	Greer	South Carolina	United States	29651
32	Novo Nordisk Investigational Site	Spartanburg	South Carolina	United States	29303
33	Novo Nordisk Investigational Site	Humboldt	Tennessee	United States	38343
34	Novo Nordisk Investigational Site	Kingsport	Tennessee	United States	37660
35	Novo Nordisk Investigational Site	Houston	Texas	United States	77008
36	Novo Nordisk Investigational Site	Katy	Texas	United States	77450
37	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78215
38	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78240
39	Novo Nordisk Investigational Site	Newport News	Virginia	United States	23606
40	Novo Nordisk Investigational Site	Richmond	Virginia	United States	23294
41	Novo Nordisk Investigational Site	Linz		Austria	4021
42	Novo Nordisk Investigational Site	Mödling		Austria	2340
43	Novo Nordisk Investigational Site	St. Stefan		Austria	8511
44	Novo Nordisk Investigational Site	Wien		Austria	1010
45	Novo Nordisk Investigational Site	Wien		Austria	1090
46	Novo Nordisk Investigational Site	Wien		Austria	1130
47	Novo Nordisk Investigational Site	Wien		Austria	1230
48	Novo Nordisk Investigational Site	Kozloduy		Bulgaria	3320
49	Novo Nordisk Investigational Site	Lukovit		Bulgaria	5770
50	Novo Nordisk Investigational Site	Ruse		Bulgaria	7000
51	Novo Nordisk Investigational Site	Sofia		Bulgaria	1784
52	Novo Nordisk Investigational Site	Varna		Bulgaria	9002
53	Novo Nordisk Investigational Site	Burnaby	British Columbia	Canada	V5G 1T4
54	Novo Nordisk Investigational Site	Coquitlam	British Columbia	Canada	V3K 3P4
55	Novo Nordisk Investigational Site	Surrey	British Columbia	Canada	V3S 2N6
56	Novo Nordisk Investigational Site	Moncton	New Brunswick	Canada	E1G 1A7
57	Novo Nordisk Investigational Site	Halifax	Nova Scotia	Canada	B3K 2M5
58	Novo Nordisk Investigational Site	Liverpool	Nova Scotia	Canada	B0T 1K0
59	Novo Nordisk Investigational Site	London	Ontario	Canada	N6G 2M1
60	Novo Nordisk Investigational Site	Waterloo	Ontario	Canada	N2J 1C4
61	Novo Nordisk Investigational Site	Olomouc, Lazce		Czechia	77900
62	Novo Nordisk Investigational Site	Plzen		Czechia	30166
63	Novo Nordisk Investigational Site	Plzen		Czechia	32600
64	Novo Nordisk Investigational Site	Praha 4		Czechia	140 46
65	Novo Nordisk Investigational Site	Trutnov		Czechia	541 01
66	Novo Nordisk Investigational Site	Budapest		Hungary	1089
67	Novo Nordisk Investigational Site	Budapest		Hungary	1135
68	Novo Nordisk Investigational Site	Debrecen		Hungary	4043
69	Novo Nordisk Investigational Site	Szombathely		Hungary	H-9700
70	Novo Nordisk Investigational Site	Zalaegerszeg		Hungary	8900
71	Novo Nordisk Investigational Site	Barnaul		Russian Federation	656024
72	Novo Nordisk Investigational Site	Barnaul		Russian Federation	656045
73	Novo Nordisk Investigational Site	Cheboksary		Russian Federation	428000
74	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	194358
75	Novo Nordisk Investigational Site	Samara		Russian Federation	443041
76	Novo Nordisk Investigational Site	St. Petersburg		Russian Federation	194354
77	Novo Nordisk Investigational Site	Belgrade		Serbia	11000
78	Novo Nordisk Investigational Site	Bratislava		Slovakia	81108
79	Novo Nordisk Investigational Site	Bratislava		Slovakia	82102
80	Novo Nordisk Investigational Site	Bratislava		Slovakia	851 01
81	Novo Nordisk Investigational Site	Dunajska Streda		Slovakia	92901
82	Novo Nordisk Investigational Site	Sabinov		Slovakia	08301
83	Novo Nordisk Investigational Site	Vranov nad Toplou		Slovakia	09301
84	Novo Nordisk Investigational Site	Zilina		Slovakia	01207

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: NCT02298192
• Other Study ID Numbers: NN9068-4056; 2012-004625-25; U1111-1135-6634
• First Posted: Nov 21, 2014
• Last Update Posted: May 23, 2017
• Last Verified: Apr 1, 2017

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 80 sites in 9 countries as follows:Austria: 6 sites; Bulgaria: 5 sites; Canada: 7 sites, Czech Republic:5 sites; Hungary: 4 sites, Russian Federation: 6 sites; Serbia: 4sites, Slovakia: 7 sites; United States: 36 sites.
Pre-assignment Detail	Stable daily treatment with metformin (≥1500 mg or max tolerated dose) ± pioglitazone (≥30 mg) for at least 90 days prior to screening

Arm/Group Title	IDegLira (1WT)	IDegLira
Arm/Group Description	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira once weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 2 fasting SMPG values measured pre-breakfast in the morning of two consecutive days corresponding to one obtained on the day before titration and one obtained on titration day.	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira twice weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 3 fasting SMPG values measured pre-breakfast in the morning of three consecutive days corresponding to one obtained on each of two days before titration and one obtained on titration day.
Period Title: Overall Study
STARTED	210	210
COMPLETED	191	204
NOT COMPLETED	19	6

Baseline Characteristics

Arm/Group Title	IDegLira (1WT)	IDegLira	Total
Arm/Group Description	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira once weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 2 fasting SMPG values measured pre-breakfast in the morning of two consecutive days corresponding to one obtained on the day before titration and one obtained on titration day.	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira twice weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 3 fasting SMPG values measured pre-breakfast in the morning of three consecutive days corresponding to one obtained on each of two days before titration and one obtained on titration day.	Total of all reporting groups
Overall Participants	210	210	420
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.6 (10.3)	57.0 (9.6)	56.8 (9.9)
Sex: Female, Male (Count of Participants)
Female	99 47.1%	98 46.7%	197 46.9%
Male	111 52.9%	112 53.3%	223 53.1%
HbA1c (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	8.2 (0.9)	8.1 (0.9)	8.1 (0.9)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in HbA1c
Description	Change in glycosylated haemoglobin A1c (HbA1c) (%) from baseline after 32 weeks of treatment.
Time Frame	Week 0, week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects. 20 subjects in the IDegLira (1WT) and 10 subjects in the IDegLira arm did not contribute to the analysis for this endpoint.

Arm/Group Title	IDegLira (1WT)	IDegLira
Arm/Group Description	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira once weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 2 fasting SMPG values measured pre-breakfast in the morning of two consecutive days corresponding to one obtained on the day before titration and one obtained on titration day.	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira twice weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 3 fasting SMPG values measured pre-breakfast in the morning of three consecutive days corresponding to one obtained on each of two days before titration and one obtained on titration day.
Measure Participants	189	200
Mean (Standard Deviation) [percentage]	-2.01 (1.09)	-2.02 (0.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IDegLira (1WT), IDegLira
	Comments	The null hypothesis was tested against the alternative hypothesis of non-inferiority as given by H0: D ≥0.30% against HA: D <0.30%.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The null hypothesis was tested against the alternative hypothesis of non-inferiority as given by H0: D ≥0.30% against HA: D <0.30%.
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment Contrast
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	HbA1c Below 7.0%
Description	Responders to HbA1c below 7% after 32 weeks of treatment.
Time Frame	Week 0, week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects. 20 subjects in the IDegLira (1WT) and 10 subjects in the IDegLira arm did not contribute to the analysis for this endpoint.

Arm/Group Title	IDegLira (1WT)	IDegLira
Arm/Group Description	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira once weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 2 fasting SMPG values measured pre-breakfast in the morning of two consecutive days corresponding to one obtained on the day before titration and one obtained on titration day.	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira twice weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 3 fasting SMPG values measured pre-breakfast in the morning of three consecutive days corresponding to one obtained on each of two days before titration and one obtained on titration day.
Measure Participants	189	200
yes	170 81%	179 85.2%
No	19 9%	21 10%

3. Secondary Outcome

Title	HbA1c Below or Equal to 6.5%
Description	Responders to HbA1c below or equal to 6.5% after 32 weeks of treatment.
Time Frame	Week 0, week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects. 20 subjects in the IDegLira (1WT) and 10 subjects in the IDegLira arm did not contribute to the analysis for this endpoint.

Arm/Group Title	IDegLira (1WT)	IDegLira
Arm/Group Description	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira once weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 2 fasting SMPG values measured pre-breakfast in the morning of two consecutive days corresponding to one obtained on the day before titration and one obtained on titration day.	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira twice weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 3 fasting SMPG values measured pre-breakfast in the morning of three consecutive days corresponding to one obtained on each of two days before titration and one obtained on titration day.
Measure Participants	189	200
yes	158	170
No	31	30

4. Secondary Outcome

Title	Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes
Description	An episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Time Frame	Week 0-32

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAS): Included all subjects receiving at least one dose of trial product. Subjects contributed to the evaluation "as treated". One subject in the IDegLira (1WT) arm did not contribute to the analysis for this endpoint.

Arm/Group Title	IDegLira (1WT)	IDegLira
Arm/Group Description	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira once weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 2 fasting SMPG values measured pre-breakfast in the morning of two consecutive days corresponding to one obtained on the day before titration and one obtained on titration day.	Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira twice weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 3 fasting SMPG values measured pre-breakfast in the morning of three consecutive days corresponding to one obtained on each of two days before titration and one obtained on titration day.
Measure Participants	209	210
Number [Number of episodes]	20	97

Adverse Events

Time Frame	Defined as an event that has onset date on or after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment. (Visit 1- Visit 36)
Adverse Event Reporting Description	Safety Analysis Set (SAS): Included all subjects receiving at least one dose of trial product. Subjects contributed to the evaluation "as treated".
Arm/Group Title	IDegLira (1WT)		IDegLira
Arm/Group Description	Subjects received IDegLira once weekly in combination with metformin alone or in combination with pioglitazone in a 1:1 manner at visit 2 and were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36 mg liraglutide), and the maximum dose was 50 dose steps (50 units IDeg/1.8 mg liraglutide).The daily dose for metformin (≥1500 mg or max tolerated dose) and pioglitazone (≥30 mg) The dose of IDegLira was to be adjusted once weekly based on the mean of 2 fasting SMPG values measured pre-breakfast in the morning of two consecutive days corresponding to one obtained on the day before titration and one obtained on the titration day. The first dose of trial product was to be administered either on the day of randomisation (visit 2) or the day after.		Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira twice weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 3 fasting SMPG values measured pre-breakfast in the morning of three consecutive days corresponding to one obtained on each of two days before titration and one obtained on titration day.
All Cause Mortality
	IDegLira (1WT)		IDegLira
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	IDegLira (1WT)		IDegLira
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/209 (3.3%)		14/210 (6.7%)
Cardiac disorders
Atrial fibrillation	0/209 (0%)	0	1/210 (0.5%)	1
Supraventricular tachycardia	1/209 (0.5%)	1	0/210 (0%)	0
Gastrointestinal disorders
Colitis	1/209 (0.5%)	1	0/210 (0%)	0
Enteritis	1/209 (0.5%)	1	0/210 (0%)	0
Umbilical hernia	0/209 (0%)	0	1/210 (0.5%)	1
General disorders
Non-cardiac chest pain	1/209 (0.5%)	1	0/210 (0%)	0
Infections and infestations
Appendicitis	0/209 (0%)	0	2/210 (1%)	2
Cellulitis	0/209 (0%)	0	1/210 (0.5%)	1
Cholecystitis infective	0/209 (0%)	0	1/210 (0.5%)	1
Gastroenteritis	0/209 (0%)	0	1/210 (0.5%)	1
Pneumonia	0/209 (0%)	0	1/210 (0.5%)	1
Post procedural infection	0/209 (0%)	0	1/210 (0.5%)	1
Urinary tract infection	0/209 (0%)	0	1/210 (0.5%)	1
Injury, poisoning and procedural complications
Meniscus injury	0/209 (0%)	0	1/210 (0.5%)	1
Investigations
Blood glucose increased	0/209 (0%)	0	1/210 (0.5%)	1
Metabolism and nutrition disorders
Hyperglycaemia	1/209 (0.5%)	1	0/210 (0%)	0
Musculoskeletal and connective tissue disorders
Spinal pain	0/209 (0%)	0	1/210 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial adenocarcinoma	1/209 (0.5%)	1	0/210 (0%)	0
Nervous system disorders
Migraine	1/209 (0.5%)	1	0/210 (0%)	0
Renal and urinary disorders
Haematuria	0/209 (0%)	0	1/210 (0.5%)	1
Nephrolithiasis	0/209 (0%)	0	2/210 (1%)	2
Vascular disorders
Circulatory collapse	0/209 (0%)	0	1/210 (0.5%)	1
Hypotension	1/209 (0.5%)	1	0/210 (0%)	0
Peripheral arterial occlusive disease	1/209 (0.5%)	2	0/210 (0%)	0
Other (Not Including Serious) Adverse Events
	IDegLira (1WT)		IDegLira
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/209 (11.5%)		19/210 (9%)
Gastrointestinal disorders
Nausea	11/209 (5.3%)	16	11/210 (5.2%)	20
Infections and infestations
Nasopharyngitis	13/209 (6.2%)	16	9/210 (4.3%)	13

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 scientific publications may be prepared collaboratively by the investigator (s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for upto 60 days to protect intellectual property.