A Clinical Trial Comparing Efficacy and Safety of Insulin Degludec/Liraglutide (IDegLira) Versus Basal-bolus Therapy in Subjects With Type 2 Diabetes Mellitus

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02420262
• Collaborator: (none)
• Enrollment: 506
• Locations: 117
• Arms: 2
• Actual Duration (Months): 14.4
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This trial is conducted globally. The aim of this trial is to compare efficacy and safety of insulin degludec/liraglutide (IDegLira) versus basal-bolus therapy in combination with metformin in subjects with type 2 diabetes mellitus.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 506 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) Versus Basal-bolus Therapy in Subjects With Type 2 Diabetes Mellitus
• Actual Study Start Date: Jul 26, 2015
• Actual Primary Completion Date: Oct 5, 2016
• Actual Study Completion Date: Oct 5, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IDegLira	Drug: insulin degludec/liraglutide; Once daily injected s.c./subcutaneously (under the skin) in combination with metformin.
Active Comparator: IGlar plus IAsp	Drug: insulin glargine; Once daily injected s.c./subcutaneously (under the skin) in combination with metformin.; Drug: insulin aspart; Injected s.c./subcutaneously (under the skin) before each main meal.

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c (Glycosylated Haemoglobin) [Week 0, Week 26]

   Change in HbA1c values after 26 weeks of treatment.

Secondary Outcome Measures

1. Number of Treatment Emergent Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemic Episodes. [Weeks 0-26]

   Severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe and/or BG confirmed by a plasma glucose value of <56 mg/dL (3.1 mmol/L), with symptoms consistent with hypoglycaemia.

2. Change in Body Weight [Week 0, Week 26]

   Change in body weight after 26 weeks of treatment.

3. Responder for HbA1c Below 7.0% [After 26 weeks of treatment]

   Number of subjects with HbA1c below 7% after 26 weeks of treatment.

4. Responder for HbA1c Below or Equal to 6.5 % [After 26 weeks of treatment]

   Number of subjects with HbA1c below 6.5% after 26 weeks of treatment.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female, age at least 18 years at the time of signing informed consent

• Type 2 diabetes subjects (diagnosed clinically) at least 6 months prior to screening

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

• Current treatment with IGlar (insulin glargine) for at least 90 calendar days prior to screening

• Stable daily dose of IGlar between 20 units and 50 units (both inclusive) for at least 56 calendar days prior to screening. Individual fluctuations of plus/minus 10% within the 56 calendar days prior to screening are acceptable, however on the day of screening total daily dose should be within the range of 20 units-50 units both inclusive

• Stable daily dose of metformin (at least 1500 mg or max tolerated dose) for at least 90 calendar days prior to screening

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

Exclusion Criteria:

• Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 90 calendar days before screening

• Anticipated initiation or change in concomitant medications in excess of 14 calendar days known to affect weight or glucose metabolism, such as weight loss/modifying (e.g.; sibutramine, orlistat, thyroid hormones, corticosteroids)

• Impaired liver function, defined as alanine aminotransferase (ALT) at least 2.5 times upper limit of normal

• Renal impairment eGFR (electronic case report form) below 60 mL/min/1.73 m^2 as per CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)

• Screening calcitonin at least 50 ng/L

• History of pancreatitis (acute or chronic)

• Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Tuscumbia	Alabama	United States	35674
2	Novo Nordisk Investigational Site	Anaheim	California	United States	92801
3	Novo Nordisk Investigational Site	Bermuda Dunes	California	United States	92203
4	Novo Nordisk Investigational Site	Fresno	California	United States	93720
5	Novo Nordisk Investigational Site	Lancaster	California	United States	93534
6	Novo Nordisk Investigational Site	Lincoln	California	United States	95648
7	Novo Nordisk Investigational Site	Lomita	California	United States	90717
8	Novo Nordisk Investigational Site	Los Angeles	California	United States	90057
9	Novo Nordisk Investigational Site	Montclair	California	United States	91763
10	Novo Nordisk Investigational Site	Northridge	California	United States	91325
11	Novo Nordisk Investigational Site	San Mateo	California	United States	94401
12	Novo Nordisk Investigational Site	Ventura	California	United States	93003
13	Novo Nordisk Investigational Site	Waterbury	Connecticut	United States	06708
14	Novo Nordisk Investigational Site	Palm Harbor	Florida	United States	34684-3609
15	Novo Nordisk Investigational Site	Plantation	Florida	United States	33324
16	Novo Nordisk Investigational Site	Blackfoot	Idaho	United States	83221
17	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60607
18	Novo Nordisk Investigational Site	Skokie	Illinois	United States	60077
19	Novo Nordisk Investigational Site	Indianapolis	Indiana	United States	46254
20	Novo Nordisk Investigational Site	Metairie	Louisiana	United States	70002
21	Novo Nordisk Investigational Site	Natchitoches	Louisiana	United States	71457-5881
22	Novo Nordisk Investigational Site	Shreveport	Louisiana	United States	71105
23	Novo Nordisk Investigational Site	Rockville	Maryland	United States	20852
24	Novo Nordisk Investigational Site	Waltham	Massachusetts	United States	02453
25	Novo Nordisk Investigational Site	Billings	Montana	United States	59101
26	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89109
27	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89128
28	Novo Nordisk Investigational Site	Albuquerque	New Mexico	United States	87102
29	Novo Nordisk Investigational Site	Albany	New York	United States	12206
30	Novo Nordisk Investigational Site	Jackson Heights	New York	United States	11372
31	Novo Nordisk Investigational Site	New Windsor	New York	United States	12553
32	Novo Nordisk Investigational Site	West Seneca	New York	United States	14224
33	Novo Nordisk Investigational Site	Shelby	North Carolina	United States	28150
34	Novo Nordisk Investigational Site	Statesville	North Carolina	United States	28625
35	Novo Nordisk Investigational Site	Cincinnati	Ohio	United States	45245
36	Novo Nordisk Investigational Site	Columbus	Ohio	United States	43213
37	Novo Nordisk Investigational Site	Dayton	Ohio	United States	45439
38	Novo Nordisk Investigational Site	Mason	Ohio	United States	45040-6815
39	Novo Nordisk Investigational Site	Altoona	Pennsylvania	United States	16602
40	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19152
41	Novo Nordisk Investigational Site	Greer	South Carolina	United States	29651
42	Novo Nordisk Investigational Site	Murrells Inlet	South Carolina	United States	29576
43	Novo Nordisk Investigational Site	Kingsport	Tennessee	United States	37660
44	Novo Nordisk Investigational Site	Houston	Texas	United States	77024
45	Novo Nordisk Investigational Site	Houston	Texas	United States	77058
46	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78229
47	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77478
48	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77479
49	Novo Nordisk Investigational Site	Midlothian	Virginia	United States	23114
50	Novo Nordisk Investigational Site	Spokane	Washington	United States	99208
51	Novo Nordisk Investigational Site	Caba		Argentina	C1440AAD
52	Novo Nordisk Investigational Site	Capital Federal		Argentina	1405
53	Novo Nordisk Investigational Site	Córdoba		Argentina	X5006IKK
54	Novo Nordisk Investigational Site	Salta		Argentina	4400
55	Novo Nordisk Investigational Site	Brno		Czechia	65691
56	Novo Nordisk Investigational Site	Hradec Králové		Czechia	500 36
57	Novo Nordisk Investigational Site	Olomouc, Lazce		Czechia	77900
58	Novo Nordisk Investigational Site	Olomouc		Czechia	77900
59	Novo Nordisk Investigational Site	Pardubice		Czechia	53002
60	Novo Nordisk Investigational Site	Prostejov		Czechia	79601
61	Novo Nordisk Investigational Site	Angers		France	49000
62	Novo Nordisk Investigational Site	Bourgoin-jallieu		France	38302
63	Novo Nordisk Investigational Site	Brest		France	29609
64	Novo Nordisk Investigational Site	LA ROCHELLE cedex		France	17019
65	Novo Nordisk Investigational Site	Le Coudray		France	28630
66	Novo Nordisk Investigational Site	Le Creusot		France	71200
67	Novo Nordisk Investigational Site	MARSEILLE cedex 08		France	13285
68	Novo Nordisk Investigational Site	Marseille		France	13008
69	Novo Nordisk Investigational Site	Saint Herblain		France	44800
70	Novo Nordisk Investigational Site	Saint Priest en Jarez		France	42270
71	Novo Nordisk Investigational Site	Strasbourg		France	67098
72	Novo Nordisk Investigational Site	Venissieux		France	69200
73	Novo Nordisk Investigational Site	Athens		Greece	GR-11527
74	Novo Nordisk Investigational Site	Chalkida, Evia		Greece	GR-34100
75	Novo Nordisk Investigational Site	Ioannina		Greece	45500
76	Novo Nordisk Investigational Site	Larissa		Greece	GR-41110
77	Novo Nordisk Investigational Site	Thessaloniki		Greece	GR-54642
78	Novo Nordisk Investigational Site	Thessaloniki		Greece	GR-57001
79	Novo Nordisk Investigational Site	Budapest		Hungary	1115
80	Novo Nordisk Investigational Site	Gyula		Hungary	H-5700
81	Novo Nordisk Investigational Site	Szeged		Hungary	H-6720
82	Novo Nordisk Investigational Site	Szombathely		Hungary	H-9700
83	Novo Nordisk Investigational Site	Tatabánya		Hungary	2800
84	Novo Nordisk Investigational Site	Haifa		Israel	35152
85	Novo Nordisk Investigational Site	Holon		Israel	58100
86	Novo Nordisk Investigational Site	Jerusalem		Israel	91120
87	Novo Nordisk Investigational Site	Kfar Saba		Israel	44281
88	Novo Nordisk Investigational Site	Nahariya		Israel	22100
89	Novo Nordisk Investigational Site	Rehovot		Israel	76100
90	Novo Nordisk Investigational Site	Guadalajara	Jalisco	Mexico	44650
91	Novo Nordisk Investigational Site	Mexico City	México, D.F.	Mexico	03300
92	Novo Nordisk Investigational Site	Aguascalientes		Mexico	20230
93	Novo Nordisk Investigational Site	Durango		Mexico	34000
94	Novo Nordisk Investigational Site	Kazan		Russian Federation	420073
95	Novo Nordisk Investigational Site	Moscow		Russian Federation	117036
96	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	191119
97	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	194291
98	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	194354
99	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	199034
100	Novo Nordisk Investigational Site	Volgograd		Russian Federation	400131
101	Novo Nordisk Investigational Site	Bardejov		Slovakia	08501
102	Novo Nordisk Investigational Site	Dolny Kubin		Slovakia	02601
103	Novo Nordisk Investigational Site	Malacky		Slovakia	90101
104	Novo Nordisk Investigational Site	Poprad		Slovakia	05801
105	Novo Nordisk Investigational Site	Roznava		Slovakia	04801
106	Novo Nordisk Investigational Site	Almería		Spain	04001
107	Novo Nordisk Investigational Site	Fuenlabrada - Madrid		Spain	28942
108	Novo Nordisk Investigational Site	Pozuelo de Alarcon		Spain	28223
109	Novo Nordisk Investigational Site	Sevilla		Spain	41003
110	Novo Nordisk Investigational Site	Sevilla		Spain	41010
111	Novo Nordisk Investigational Site	Valencia		Spain	46026
112	Novo Nordisk Investigational Site	Ankara		Turkey	06100
113	Novo Nordisk Investigational Site	Ankara		Turkey	06110
114	Novo Nordisk Investigational Site	Antalya		Turkey	07058
115	Novo Nordisk Investigational Site	Istanbul		Turkey	34096
116	Novo Nordisk Investigational Site	Istanbul		Turkey	34303
117	Novo Nordisk Investigational Site	Istanbul		Turkey	34371

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: NCT02420262
• Other Study ID Numbers: NN9068-4185; 2014-003621-18; U1111-1160-6923; REec-2015-1682
• First Posted: Apr 17, 2015
• Last Update Posted: Mar 29, 2018
• Last Verified: Feb 1, 2018

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 89 sites in 12 countries: Argentina (3 sites), Czech Republic (5 sites), France (3 sites), Greece (6 sites), Hungary (3 sites), Israel (6 sites), Mexico (3 sites), Russia (7 sites), Slovakia (5 sites), Spain (6 sites), Turkey (5 sites) and United States (37 sites).
Pre-assignment Detail	Subjects with type 2 diabetes mellitus were on treatment with stable daily dose of insulin glargine (IGlar) between 20 units and 50 units (both inclusive) for at least 56 days prior to screening in combination with a stable daily dose of metformin (≥1500 mg or maximum tolerated dose) for at least 90 days prior to screening.

Arm/Group Title	IDegLira	IGlar + IAsp
Arm/Group Description	Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously once daily (OD) for a duration of 26 weeks. IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]).The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern.	Subjects received insulin glargine plus prandial insulin aspart subcutaneously for duration of 26 weeks. A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®) was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 - 6.0 mmol/L).
Period Title: Overall Study
STARTED	252	254
Exposed	252	253
COMPLETED	250	249
NOT COMPLETED	2	5

Baseline Characteristics

Arm/Group Title	IDegLira	IGlar + IAsp	Total
Arm/Group Description	Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously once daily (OD) for a duration of 26 weeks. IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]).The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern.	Subjects received insulin glargine plus prandial insulin aspart subcutaneously for duration of 26 weeks. A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®) was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 - 6.0 mmol/L).	Total of all reporting groups
Overall Participants	252	254	506
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.6 (9.0)	58.0 (8.6)	58.3 (8.8)
Sex: Female, Male (Count of Participants)
Female	142 56.3%	137 53.9%	279 55.1%
Male	110 43.7%	117 46.1%	227 44.9%
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.21 (0.76)	8.24 (0.81)	8.22 (0.78)
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	87.2 (16.0)	88.2 (17.2)	87.7 (16.6)

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c (Glycosylated Haemoglobin)
Description	Change in HbA1c values after 26 weeks of treatment.
Time Frame	Week 0, Week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation "as randomised". 8 subjects in IDegLira and 9 subjects in IGlar + IAsp arm did not contribute to the analysis for this endpoint.

Arm/Group Title	IDegLira	IGlar + IAsp
Arm/Group Description	Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously once daily (OD) for a duration of 26 weeks. IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]).The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern.	Subjects received insulin glargine plus prandial insulin aspart subcutaneously for duration of 26 weeks. A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®) was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 - 6.0 mmol/L).
Measure Participants	244	245
Least Squares Mean (Standard Error) [Percentage of glycosylated haemoglobin]	-1.48 (0.05)	-1.46 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IDegLira, IGlar + IAsp
	Comments	Change from baseline in HbA1c was analysed using a mixed model for repeated measurements with an unstructured covariance matrix. The model included treatment, visit and region as fixed factors and baseline HbA1c as covariate. Interactions between visit and all factors and the covariate were also included in the model.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority for IDegLira vs basal-bolus (IGlar + IAsp) was considered confirmed if the upper boundary of the two-sided 95% confidence interval was strictly below 0.30% or equivalent for non-inferiority using one-sided test for null hypothesis (H0): D ≥0.30% against alternative hypothesis (HA): D <0.30% was less than or equal to 2.5%, where D is the mean treatment difference (IDegLira minus basal-bolus).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment contrast
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Treatment Emergent Severe or Blood Glucose Confirmed Symptomatic Hypoglycaemic Episodes.
Description	Severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe and/or BG confirmed by a plasma glucose value of <56 mg/dL (3.1 mmol/L), with symptoms consistent with hypoglycaemia.
Time Frame	Weeks 0-26

Outcome Measure Data

Analysis Population Description

The safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product or comparator. Subjects in the safety set contributed to the evaluation "as treated". One subject in IGlar + IAsp arm did not contribute to the analysis for this endpoint.

Arm/Group Title	IDegLira	IGlar + IAsp
Arm/Group Description	Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously once daily (OD) for a duration of 26 weeks. IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]).The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern.	Subjects received insulin glargine plus prandial insulin aspart subcutaneously for duration of 26 weeks. A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®) was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 - 6.0 mmol/L).
Measure Participants	252	253
Number [Number of episodes]	129	975

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IDegLira, IGlar + IAsp
	Comments	Hypoglycaemic episodes were analysed using a negative binomial regression. The model included treatment and region as fixed factors and logarithm of the time period in which a hypoglycaemic episode considered treatment emergent as offset. The test for superiority of the confirmatory secondary endpoints was carried out only if non-inferiority of IDegLira vs basal-bolus for primary endpoint was confirmed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	Treatment ratio
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; 0.08 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Superiority for IDegLira vs basal-bolus was considered confirmed if the 95% confidence interval for the treatment rate ratio was entirely below 1.0.

3. Secondary Outcome

Title	Change in Body Weight
Description	Change in body weight after 26 weeks of treatment.
Time Frame	Week 0, Week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation "as randomised". 08 subjects in both IDegLira and IGlar + IAsp arm did not contribute to the analysis for this endpoint.

Arm/Group Title	IDegLira	IGlar + IAsp
Arm/Group Description	Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously once daily (OD) for a duration of 26 weeks. IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]).The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern.	Subjects received insulin glargine plus prandial insulin aspart subcutaneously for duration of 26 weeks. A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®) was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 - 6.0 mmol/L).
Measure Participants	244	246
Least Squares Mean (Standard Error) [kg]	-0.93 (0.22)	2.64 (0.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IDegLira, IGlar + IAsp
	Comments	Body weight measurements were analysed using a linear mixed model with an unstructured covariance matrix. The model included treatment, visit and region as fixed factors and baseline bodyweight as covariate. Interactions between visit and all factors and the covariate were also included in the model. The test for superiority of the confirmatory secondary endpoints was carried out only if non-inferiority of IDegLira vs basal-bolus for primary endpoint was confirmed.
	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	-3.57
	Confidence Interval	(2-Sided) 95%; -4.19 to -2.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Superiority for IDegLira vs basal-bolus was considered confirmed if the 95% confidence interval for the treatment difference was below 0 or equal to zero.

4. Secondary Outcome

Title	Responder for HbA1c Below 7.0%
Description	Number of subjects with HbA1c below 7% after 26 weeks of treatment.
Time Frame	After 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation "as randomised". 14 subjects in IDegLira and 21 subjects in IGlar + IAsp arm did not contribute to the analysis for this endpoint.

Arm/Group Title	IDegLira	IGlar + IAsp
Arm/Group Description	Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously once daily (OD) for a duration of 26 weeks. IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]).The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern.	Subjects received insulin glargine plus prandial insulin aspart subcutaneously for duration of 26 weeks. A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®) was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 - 6.0 mmol/L).
Measure Participants	238	233
Yes	157 62.3%	156 61.4%
No	81 32.1%	77 30.3%

5. Secondary Outcome

Title	Responder for HbA1c Below or Equal to 6.5 %
Description	Number of subjects with HbA1c below 6.5% after 26 weeks of treatment.
Time Frame	After 26 weeks of treatment

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation "as randomised". 14 subjects in IDegLira and 21 subjects in IGlar + IAsp arm did not contribute to the analysis for this endpoint.

Arm/Group Title	IDegLira	IGlar + IAsp
Arm/Group Description	Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously once daily (OD) for a duration of 26 weeks. IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]).The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern.	Subjects received insulin glargine plus prandial insulin aspart subcutaneously for duration of 26 weeks. A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®) was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 - 6.0 mmol/L).
Measure Participants	238	233
Yes	118 46.8%	104 40.9%
No	120 47.6%	129 50.8%

Adverse Events

Time Frame	Adverse events (AEs) were collected from the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment (26 weeks + 7 days of follow-up).
Adverse Event Reporting Description	The safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product or comparator. Subjects in the safety set contributed to the evaluation "as treated".
Arm/Group Title	IDegLira		IGlar + IAsp
Arm/Group Description	Insulin Degludec/Liraglutide (IDegLira: 100 U/3.6 mg per mL) was injected subcutaneously once daily (OD) for a duration of 26 weeks. IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]).The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern.		Subjects received insulin glargine plus prandial insulin aspart subcutaneously for duration of 26 weeks. A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®) was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 - 6.0 mmol/L).
All Cause Mortality
	IDegLira		IGlar + IAsp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	IDegLira		IGlar + IAsp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/252 (4.8%)		10/253 (4%)
Cardiac disorders
Angina unstable	1/252 (0.4%)	1	0/253 (0%)	0
Atrial fibrillation	1/252 (0.4%)	1	0/253 (0%)	0
Atrial flutter	1/252 (0.4%)	1	0/253 (0%)	0
Cardiac failure	1/252 (0.4%)	1	0/253 (0%)	0
Silent myocardial infarction	0/252 (0%)	0	1/253 (0.4%)	1
Eye disorders
Retinal detachment	1/252 (0.4%)	1	0/253 (0%)	0
Gastrointestinal disorders
Anal fistula	0/252 (0%)	0	1/253 (0.4%)	1
Gastritis	0/252 (0%)	0	1/253 (0.4%)	1
General disorders
Chest pain	1/252 (0.4%)	1	0/253 (0%)	0
Hepatobiliary disorders
Hepatic cyst	1/252 (0.4%)	1	0/253 (0%)	0
Infections and infestations
Diabetic foot infection	1/252 (0.4%)	1	0/253 (0%)	0
Gastroenteritis	1/252 (0.4%)	1	0/253 (0%)	0
Pneumonia	0/252 (0%)	0	1/253 (0.4%)	1
Postoperative wound infection	1/252 (0.4%)	1	1/253 (0.4%)	1
Staphylococcal bacteraemia	1/252 (0.4%)	1	0/253 (0%)	0
Metabolism and nutrition disorders
Hypoglycaemia	1/252 (0.4%)	1	0/253 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/252 (0%)	0	1/253 (0.4%)	1
Osteoarthritis	0/252 (0%)	0	1/253 (0.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/252 (0%)	0	1/253 (0.4%)	1
Renal and urinary disorders
Stag horn calculus	1/252 (0.4%)	1	0/253 (0%)	0
Reproductive system and breast disorders
Metrorrhagia	0/252 (0%)	0	1/253 (0.4%)	1
Skin and subcutaneous tissue disorders
Diabetic foot	0/252 (0%)	0	1/253 (0.4%)	1
Vascular disorders
Embolism arterial	0/252 (0%)	0	1/253 (0.4%)	1
Other (Not Including Serious) Adverse Events
	IDegLira		IGlar + IAsp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/252 (33.3%)		79/253 (31.2%)
Eye disorders
Diabetic retinopathy	9/252 (3.6%)	9	14/253 (5.5%)	15
Gastrointestinal disorders
Diarrhoea	16/252 (6.3%)	24	10/253 (4%)	17
Nausea	28/252 (11.1%)	37	4/253 (1.6%)	4
Infections and infestations
Influenza	18/252 (7.1%)	21	12/253 (4.7%)	13
Nasopharyngitis	12/252 (4.8%)	12	30/253 (11.9%)	35
Upper respiratory tract infection	15/252 (6%)	15	17/253 (6.7%)	19
Nervous system disorders
Headache	14/252 (5.6%)	17	18/253 (7.1%)	23

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 manuscripts for publication will be prepared collaboratively between Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for less than 60 days to protect intellectual property.