Efficacy and Safety of Liraglutide Versus Placebo as add-on to Existing Diabetes Medication in Subjects With Type 2 Diabetes and Moderate Renal Impairment

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01620489
• Collaborator: (none)
• Enrollment: 279
• Locations: 97
• Arms: 2
• Actual Duration (Months): 14.2
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This trial is conducted in Europe and the United States of America (USA). The aim of this trial is to investigate the efficacy and safety of liraglutide in subjects with type 2 diabetes and moderate renal impairment.

The trial medication will be add-on to the subject's stable pre-trial OAD and/or insulin regimen.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 279 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Liraglutide Versus Placebo as add-on to Existing Diabetes Medication in Subjects With Type 2 Diabetes and Moderate Renal Impairment. A 26-week Double-blind Placebo-controlled, Randomised, Multicentre, Multi-national, Parallel-group Trial
• Actual Study Start Date: Jun 14, 2012
• Actual Primary Completion Date: Aug 20, 2013
• Actual Study Completion Date: Aug 20, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lira 1.8 mg	Drug: liraglutide; 1.8 mg administered once daily subcutaneously (s.c., under the skin) as add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen.
Placebo Comparator: Placebo	Drug: placebo; Administered once daily subcutaneously (s.c., under the skin) as add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen.

Outcome Measures

Primary Outcome Measures

1. Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in HbA1c (%) (Glycosylated Haemoglobin) [Week 0, Week 26]

   Calculated as the estimated mean change from baseline in HbA1c (%) after 26 Weeks of treatment based on the statistical model.

Secondary Outcome Measures

1. Estimated Proportion of Responders Achieving HbA1c <7.0% and no Weight Gain After 26 Weeks of Treatment [At week 26]

   Calculated as estimated percentage of subjects achieving HbA1c <7.0% and no weight gain after 26 weeks of treatment based on the statistical model.

2. Estimated Proportion of Responders Achieving HbA1c <7.0% and no Minor or Severe Hypoglycaemic Episodes After 26 Weeks of Treatment [At week 26]

   Calculated as estimated percentage of subjects achieving HbA1c <7.0% and no minor or severe hypoglycaemic episodes observed within 26 weeks of treatment based on the statistical model.

3. Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Self-measured Plasma Glucose (SMPG) 7-point Profiles [Week 0, week 26]

   SMPG was measured before and 90 minutes after breakfast, lunch and dinner and at bedtime at Week 0, 12 and 26. A summary measure of the 7 values was derived for each applicable visit as the area under the curve divided by the period of time elapsed between the first and last measurement. The change from baseline to week 26 was estimated using the statistical model.

4. Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Body Mass Index (BMI) [Week 0, week 26]

   Calculated as estimated mean change in BMI (kg/m˄2) from baseline to Week 26 based on the statistical model.

5. Estimated Mean Ratio to Baseline and Observed Coefficient of Variation in Renal Function-estimated Glomerular Filtration Rate (eGFR) (to Check How Well the Kidneys Are Functioning Using Modification of Diet in Renal Disease (MDRD) Formula) [Week 0, week 26]

   Calculated as the estimated ratio to baseline in eGFR (mL/min/1.73m˄2) after 26 Weeks of treatment based on the statistical model.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects diagnosed with type 2 diabetes with stable diabetes treatment (unchanged medication and unchanged dose) for 90 days prior to the screening visit including: Monotherapy or any duo-combinations of metformin and/or SUs and/or pioglitazone. Metformin should be used with caution in subjects with moderate renal failure and must be used in accordance with local metformin labelling or guidelines. Or Monotherapy or any combinations of metformin and/or pioglitazone and/or basal or premix insulin. Insulin adjustments (total daily dose) below or equal to 10% within 90 days prior to the screening visit as confirmed by the investigator are acceptable. Metformin should be used with caution in subjects with moderate renal failure and must be used in accordance with local metformin labelling or guidelines. Combination of pioglitazone and insulin should be used with caution and according to local labelling or guidelines

• HbA1c 7-10% (both inclusive)

• Moderate renal impairment diagnosed more than 90 days prior to the screening visit and confirmed by an eGFR (glomerular filtration rate) of 30-59 mL/min/1.73 m2 per MDRD (modification of diet in renal disease) formula at the screening visit

• Body Mass Index (BMI) 20-45 kg/m^2 (both inclusive)

Exclusion Criteria:

• Recurrent severe hypoglycaemia or hypoglycaemic unawareness as judged by the investigator

• Treatment with antidiabetic medication(s) other than stated in the inclusion criteria in a period of 90 days prior to screening. Previous short-term (below or equal to 7 days in total) treatment with rapid-or short-acting insulin in connection with intercurrent illness is allowed at the discretion of the investigator

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

• History of chronic pancreatitis or idiopathic acute pancreatitis

• Within the past 180 days any of the following: Episode of unstable angina, acute coronary event, cerebral stroke/transient ischemic attack (TIA) or other significant cardiovascular event (including e.g. arrhythmias or conduction delays on ECG (electrocardiogram))

• Heart failure defined as New York Heart Association (NYHA) class IV

• A systolic blood pressure above or equal to 180 mmHg or a diastolic blood pressure above or equal to 100 mmHg

• Rapidly progressing renal disease (e.g., acute glomerulonephritis) at the discretion of the investigator

• Use of immunosuppressive treatment within 90 days prior to screening

• Diagnosis or treatment for cancer in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer)

• Proliferative retinopathy or maculopathy requiring acute treatment as judged by the investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Concord	California	United States	94520
2	Novo Nordisk Investigational Site	La Jolla	California	United States	92037
3	Novo Nordisk Investigational Site	Los Angeles	California	United States	90057
4	Novo Nordisk Investigational Site	Monterey	California	United States	93940
5	Novo Nordisk Investigational Site	San Diego	California	United States	92111
6	Novo Nordisk Investigational Site	San Ramon	California	United States	94583
7	Novo Nordisk Investigational Site	Torrance	California	United States	90502
8	Novo Nordisk Investigational Site	Tustin	California	United States	92780
9	Novo Nordisk Investigational Site	Ventura	California	United States	93003
10	Novo Nordisk Investigational Site	Golden	Colorado	United States	80401
11	Novo Nordisk Investigational Site	Boynton Beach	Florida	United States	33472
12	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32216
13	Novo Nordisk Investigational Site	Miami	Florida	United States	33156
14	Novo Nordisk Investigational Site	Pembroke Pines	Florida	United States	33027
15	Novo Nordisk Investigational Site	Plantation	Florida	United States	33324
16	Novo Nordisk Investigational Site	Saint Petersburg	Florida	United States	33711
17	Novo Nordisk Investigational Site	Atlanta	Georgia	United States	30303
18	Novo Nordisk Investigational Site	Roswell	Georgia	United States	30076
19	Novo Nordisk Investigational Site	Avon	Indiana	United States	46123
20	Novo Nordisk Investigational Site	Franklin	Indiana	United States	46131
21	Novo Nordisk Investigational Site	Greenfield	Indiana	United States	46140
22	Novo Nordisk Investigational Site	Muncie	Indiana	United States	47304
23	Novo Nordisk Investigational Site	Slidell	Louisiana	United States	70461-4231
24	Novo Nordisk Investigational Site	Rockville	Maryland	United States	20852
25	Novo Nordisk Investigational Site	Springfield	Massachusetts	United States	01199
26	Novo Nordisk Investigational Site	Buckley	Michigan	United States	49620
27	Novo Nordisk Investigational Site	Southfield	Michigan	United States	48034-7661
28	Novo Nordisk Investigational Site	Great Falls	Montana	United States	59405
29	Novo Nordisk Investigational Site	Nashua	New Hampshire	United States	03063
30	Novo Nordisk Investigational Site	Rosedale	New York	United States	11422
31	Novo Nordisk Investigational Site	Staten Island	New York	United States	10301
32	Novo Nordisk Investigational Site	Greenville	North Carolina	United States	27834
33	Novo Nordisk Investigational Site	Mooresville	North Carolina	United States	28117
34	Novo Nordisk Investigational Site	Franklin	Ohio	United States	45005
35	Novo Nordisk Investigational Site	Mason	Ohio	United States	45040-6815
36	Novo Nordisk Investigational Site	Wadsworth	Ohio	United States	44281-9236
37	Novo Nordisk Investigational Site	Oklahoma City	Oklahoma	United States	73104
38	Novo Nordisk Investigational Site	McMurray	Pennsylvania	United States	15317
39	Novo Nordisk Investigational Site	Norristown	Pennsylvania	United States	19401
40	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19107
41	Novo Nordisk Investigational Site	East Providence	Rhode Island	United States	02914
42	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37404-1192
43	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37411
44	Novo Nordisk Investigational Site	Kingsport	Tennessee	United States	37660
45	Novo Nordisk Investigational Site	Amarillo	Texas	United States	79106
46	Novo Nordisk Investigational Site	Lubbock	Texas	United States	79423
47	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77479
48	Novo Nordisk Investigational Site	Newport News	Virginia	United States	23606
49	Novo Nordisk Investigational Site	Richmond	Virginia	United States	23219
50	Novo Nordisk Investigational Site	Richmond	Virginia	United States	23294
51	Novo Nordisk Investigational Site	Richmond	Virginia	United States	23298
52	Novo Nordisk Investigational Site	Winchester	Virginia	United States	22601
53	Novo Nordisk Investigational Site	Milwaukee	Wisconsin	United States	53209
54	Novo Nordisk Investigational Site	Brest		France	29609
55	Novo Nordisk Investigational Site	LA ROCHE-sur-YON cedex 9		France	85295
56	Novo Nordisk Investigational Site	LA ROCHELLE cedex		France	17019
57	Novo Nordisk Investigational Site	Pointe À Pitre		France	97159
58	Novo Nordisk Investigational Site	Strasbourg		France	67000
59	Novo Nordisk Investigational Site	Bialystok		Poland	15-381
60	Novo Nordisk Investigational Site	Bialystok		Poland	15-435
61	Novo Nordisk Investigational Site	Gdansk		Poland	80-546
62	Novo Nordisk Investigational Site	Katowice		Poland	40-767
63	Novo Nordisk Investigational Site	Krakow		Poland	31-261
64	Novo Nordisk Investigational Site	Poznan		Poland	60-111
65	Novo Nordisk Investigational Site	Poznan		Poland	60-569
66	Novo Nordisk Investigational Site	Zabrze		Poland	41-800
67	Novo Nordisk Investigational Site	Barnaul		Russian Federation	656045
68	Novo Nordisk Investigational Site	Kazan		Russian Federation	420043
69	Novo Nordisk Investigational Site	Kursk		Russian Federation	305035
70	Novo Nordisk Investigational Site	Moscow		Russian Federation	117036
71	Novo Nordisk Investigational Site	Moscow		Russian Federation	123448
72	Novo Nordisk Investigational Site	Moscow		Russian Federation	127411
73	Novo Nordisk Investigational Site	Nizhniy Novgorod		Russian Federation	603126
74	Novo Nordisk Investigational Site	Penza		Russian Federation	440026
75	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	194358
76	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	195257
77	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	199034
78	Novo Nordisk Investigational Site	Samara		Russian Federation	443067
79	Novo Nordisk Investigational Site	Saratov		Russian Federation	410031
80	Novo Nordisk Investigational Site	Saratov		Russian Federation	410039
81	Novo Nordisk Investigational Site	Saratov		Russian Federation	410053
82	Novo Nordisk Investigational Site	Smolensk		Russian Federation	214019
83	Novo Nordisk Investigational Site	Volgograd		Russian Federation	400138
84	Novo Nordisk Investigational Site	Kharkiv		Ukraine	61000
85	Novo Nordisk Investigational Site	Kiev		Ukraine	04053
86	Novo Nordisk Investigational Site	Kyiv		Ukraine	04114
87	Novo Nordisk Investigational Site	Vinnytsia		Ukraine	21010
88	Novo Nordisk Investigational Site	Zaporizhia		Ukraine	69600
89	Novo Nordisk Investigational Site	Bristol		United Kingdom	BS10 5NB
90	Novo Nordisk Investigational Site	Dundee		United Kingdom	DD1 9SY
91	Novo Nordisk Investigational Site	Edinburgh		United Kingdom	EH4 2XU
92	Novo Nordisk Investigational Site	Hull		United Kingdom	HU3 2RW
93	Novo Nordisk Investigational Site	Leicester		United Kingdom	LE5 4PW
94	Novo Nordisk Investigational Site	Letchworth		United Kingdom	SG6 4UB
95	Novo Nordisk Investigational Site	London		United Kingdom	E1 2EF
96	Novo Nordisk Investigational Site	London		United Kingdom	SE5 9RT
97	Novo Nordisk Investigational Site	Swansea		United Kingdom	SA6 6NL

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: NCT01620489
• Other Study ID Numbers: NN2211-3916; 2011-002968-24; U1111-1122-3303
• First Posted: Jun 15, 2012
• Last Update Posted: Mar 19, 2019
• Last Verified: Mar 1, 2019

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

Study Results

Participant Flow

Recruitment Details	This trial was conducted in France, Poland, Russian Federation, Ukraine, United Kingdom, and the United States of America.

Arm/Group Title	Lira 1.8 mg	Placebo
Arm/Group Description	Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).	Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).
Period Title: Overall Study
STARTED	140	139
Exposed	140	137
COMPLETED	105	105
NOT COMPLETED	35	34

Baseline Characteristics

Arm/Group Title	Lira 1.8 mg	Placebo	Total
Arm/Group Description	Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).	Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).	Total of all reporting groups
Overall Participants	140	137	277
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.0 (8.3)	66.3 (8.0)	67.2 (8.2)
Sex: Female, Male (Count of Participants)
Female	65 46.4%	72 52.6%	137 49.5%
Male	75 53.6%	65 47.4%	140 50.5%
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	9.48 (3.270)	9.27 (2.842)	9.38 (3.061)
Glycosylated haemoglobin (%)(HbA1c) (Percent (%) glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent (%) glycosylated haemoglobin]	8.08 (0.792)	8.00 (0.853)	8.04 (0.823)

Outcome Measures

1. Primary Outcome

Title	Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in HbA1c (%) (Glycosylated Haemoglobin)
Description	Calculated as the estimated mean change from baseline in HbA1c (%) after 26 Weeks of treatment based on the statistical model.
Time Frame	Week 0, Week 26

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) included all randomised subjects that received at least one dose of the study medication. A total of 14 subjects in the FAS did not contribute to the analysis due to missing data.

Arm/Group Title	Lira 1.8 mg	Placebo
Arm/Group Description	Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).	Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).
Measure Participants	127	136
Mean (Standard Deviation) [percentage (%)]	-1.05 (0.8944)	-0.38 (0.8797)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira 1.8 mg, Placebo
	Comments	The null hypothesis of no treatment difference was tested using a two-sided test based on a mixed model repeated measurement (MMRM) analysis. The model included treatment, country, stratification groups (6 groups from cross-classifying renal function category (2 levels: eGFR<45 and ≥45 mL/min) and the background insulin treatment category (3 levels: basal, premix or no insulin)) as fixed effects factors and baseline HbA1c as a covariate, all nested within week.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Adjustment for multiple comparisons was not used since there was only one primary endpoint.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference
	Estimated Value	-0.66
	Confidence Interval	() 95%; -0.90 to -0.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Estimated Proportion of Responders Achieving HbA1c <7.0% and no Weight Gain After 26 Weeks of Treatment
Description	Calculated as estimated percentage of subjects achieving HbA1c <7.0% and no weight gain after 26 weeks of treatment based on the statistical model.
Time Frame	At week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects that received at least one dose of study medication. A total of 14 subjects in the FAS did not contribute to the analysis due to missing data.

Arm/Group Title	Lira 1.8 mg	Placebo
Arm/Group Description	Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).	Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).
Measure Participants	127	136
Number [percentage of patients]	46.03	15.99

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira 1.8 mg, Placebo
	Comments	Analysed by a logistic regression model with treatment, country and stratification groups as fixed effects and HbA1c and body weight at baseline as covariates. No weight gain was defined as change from baseline to Week 26 in body weight ≤0 kg.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Not adjusted for multiple comparisons
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Estimated odds ratio
	Estimated Value	4.48
	Confidence Interval	() 95%; 2.46 to 8.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Estimated Proportion of Responders Achieving HbA1c <7.0% and no Minor or Severe Hypoglycaemic Episodes After 26 Weeks of Treatment
Description	Calculated as estimated percentage of subjects achieving HbA1c <7.0% and no minor or severe hypoglycaemic episodes observed within 26 weeks of treatment based on the statistical model.
Time Frame	At week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects that received at least one dose of study medication. A total of 14 subjects in the FAS did not contribute to the analysis due to missing data.

Arm/Group Title	Lira 1.8 mg	Placebo
Arm/Group Description	Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).	Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).
Measure Participants	127	136
Number [percentage of patients]	33.23	11.23

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira 1.8 mg, Placebo
	Comments	Analysed by a logistic regression model with treatment, country and stratification groups as fixed effects and HbA1c at baseline as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Not adjusted for multiple comparisons
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Estimated odds ratio
	Estimated Value	3.94
	Confidence Interval	() 95%; 2.12 to 7.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Self-measured Plasma Glucose (SMPG) 7-point Profiles
Description	SMPG was measured before and 90 minutes after breakfast, lunch and dinner and at bedtime at Week 0, 12 and 26. A summary measure of the 7 values was derived for each applicable visit as the area under the curve divided by the period of time elapsed between the first and last measurement. The change from baseline to week 26 was estimated using the statistical model.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects that received at least one dose of study medication. A total of 46 subjects in the FAS did not contribute to the analysis due to missing data.

Arm/Group Title	Lira 1.8 mg	Placebo
Arm/Group Description	Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).	Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).
Measure Participants	109	122
Mean (Standard Deviation) [mmol/L]	-1.59 (2.480)	-0.51 (2.391)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira 1.8 mg, Placebo
	Comments	Mean change from baseline in the 7-point profile (SMPG) after 26 weeks treatment was analysed using an MMRM model with treatment, country and stratification groups as fixed effects and baseline as a covariate, all nested within visit.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Not adjusted for multiple comparisons
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference
	Estimated Value	-1.08
	Confidence Interval	() 95%; -1.58 to -0.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Body Mass Index (BMI)
Description	Calculated as estimated mean change in BMI (kg/m˄2) from baseline to Week 26 based on the statistical model.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects that received at least one dose of study medication. A total of 14 subjects in the FAS did not contribute to the analysis due to missing data.

Arm/Group Title	Lira 1.8 mg	Placebo
Arm/Group Description	Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).	Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).
Measure Participants	127	136
Mean (Standard Deviation) [kg/m^2]	-0.88 (1.3214)	-0.38 (1.1679)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira 1.8 mg, Placebo
	Comments	Change from baseline in BMI (kg/m˄2) after 26 weeks treatment was analysed separately using an MMRM analysis model with treatment, country and stratification groups as fixed effects and baseline as a covariate, all nested within visit.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0022
	Comments
	Method	Mixed Models Analysis
	Comments	Not adjusted for multiple comparisons
Method of Estimation	Estimation Parameter	Estimated treatment difference
	Estimated Value	-0.51
	Confidence Interval	() 95%; -0.83 to -0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Estimated Mean Ratio to Baseline and Observed Coefficient of Variation in Renal Function-estimated Glomerular Filtration Rate (eGFR) (to Check How Well the Kidneys Are Functioning Using Modification of Diet in Renal Disease (MDRD) Formula)
Description	Calculated as the estimated ratio to baseline in eGFR (mL/min/1.73m˄2) after 26 Weeks of treatment based on the statistical model.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

Safety analysis set included all subjects receiving at least one dose of the trial product. A total of 8 subjects in the safety analysis set did not contribute to the analysis due to missing data.

Arm/Group Title	Lira 1.8 mg	Placebo
Arm/Group Description	Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).	Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).
Measure Participants	132	137
Geometric Mean (Geometric Coefficient of Variation) [mL/min/1.73m˄2]	0.99 (0.17)	1.01 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira 1.8 mg, Placebo
	Comments	The ratio to baseline in eGFR (mL/min/1.73m˄2) after 26 weeks treatment was estimated based on log-transformed data for changes from baseline. The responses were analysed using an MMRM model with treatment, country and stratification groups as fixed effects and log-transformed baseline as a covariate, all nested within visit. The resulting estimates were back-transformed to the original scale.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	= 0.3575
	Comments	Not adjusted for multiple comparisons
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment ratio
	Estimated Value	0.98
	Confidence Interval	() 95%; 0.94 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	The adverse events were collected from Week 0 to Week 27±3 Days
Adverse Event Reporting Description	Safety analysis set included all subjects receiving at least one dose of the investigational product.
Arm/Group Title	Lira 1.8 mg		Placebo
Arm/Group Description	Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).		Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone).
All Cause Mortality
	Lira 1.8 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lira 1.8 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/140 (10%)		15/137 (10.9%)
Blood and lymphatic system disorders
Anaemia	0/140 (0%)	0	1/137 (0.7%)	1
Cardiac disorders
Acute myocardial infarction	1/140 (0.7%)	1	1/137 (0.7%)	1
Cardiac failure congestive	1/140 (0.7%)	1	0/137 (0%)	0
Left ventricular failure	1/140 (0.7%)	1	0/137 (0%)	0
Myocardial infarction	1/140 (0.7%)	1	0/137 (0%)	0
Gastrointestinal disorders
Abdominal pain lower	0/140 (0%)	0	1/137 (0.7%)	1
Gastric ulcer haemorrhage	0/140 (0%)	0	1/137 (0.7%)	1
Gastrointestinal haemorrhage	0/140 (0%)	0	1/137 (0.7%)	1
General disorders
Chest pain	1/140 (0.7%)	1	0/137 (0%)	0
Hepatobiliary disorders
Autoimmune hepatitis	0/140 (0%)	0	1/137 (0.7%)	1
Cholecystitis	1/140 (0.7%)	1	0/137 (0%)	0
Infections and infestations
Arteriosclerotic gangrene	0/140 (0%)	0	1/137 (0.7%)	1
Biliary sepsis	1/140 (0.7%)	1	0/137 (0%)	0
Meningitis herpes	1/140 (0.7%)	1	0/137 (0%)	0
Osteomyelitis	0/140 (0%)	0	1/137 (0.7%)	1
Pneumonia	1/140 (0.7%)	1	0/137 (0%)	0
Injury, poisoning and procedural complications
Fall	0/140 (0%)	0	1/137 (0.7%)	1
Spinal cord injury lumbar	0/140 (0%)	0	1/137 (0.7%)	1
Investigations
C-reactive protein increased	1/140 (0.7%)	1	0/137 (0%)	0
Glomerular filtration rate decreased	0/140 (0%)	0	1/137 (0.7%)	1
Urine albumin/creatinine ratio increased	1/140 (0.7%)	1	0/137 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus	1/140 (0.7%)	1	1/137 (0.7%)	1
Diabetic ketoacidosis	1/140 (0.7%)	1	0/137 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	0/140 (0%)	0	1/137 (0.7%)	1
Benign neoplasm of cervix uteri	0/140 (0%)	0	1/137 (0.7%)	1
Endometrial adenocarcinoma	0/140 (0%)	0	1/137 (0.7%)	1
Nervous system disorders
Cerebral haemorrhage	1/140 (0.7%)	1	0/137 (0%)	0
Cerebrovascular accident	1/140 (0.7%)	1	0/137 (0%)	0
Syncope	2/140 (1.4%)	2	0/137 (0%)	0
Renal and urinary disorders
Renal impairment	1/140 (0.7%)	1	1/137 (0.7%)	1
Urethral stenosis	0/140 (0%)	0	1/137 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/140 (0.7%)	1	0/137 (0%)	0
Pulmonary fibrosis	1/140 (0.7%)	1	0/137 (0%)	0
Pulmonary oedema	1/140 (0.7%)	1	0/137 (0%)	0
Surgical and medical procedures
Colectomy	0/140 (0%)	0	1/137 (0.7%)	1
Vascular disorders
Arteriosclerosis	0/140 (0%)	0	1/137 (0.7%)	1
Poor peripheral circulation	0/140 (0%)	0	1/137 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Lira 1.8 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/140 (52.1%)		49/137 (35.8%)
Gastrointestinal disorders
Constipation	8/140 (5.7%)	9	2/137 (1.5%)	2
Diarrhoea	10/140 (7.1%)	13	4/137 (2.9%)	6
Nausea	30/140 (21.4%)	39	6/137 (4.4%)	10
Vomiting	17/140 (12.1%)	18	3/137 (2.2%)	4
Infections and infestations
Nasopharyngitis	7/140 (5%)	7	16/137 (11.7%)	17
Upper respiratory tract infection	4/140 (2.9%)	4	7/137 (5.1%)	8
Investigations
Glomerular filtration rate decreased	9/140 (6.4%)	10	7/137 (5.1%)	14
Lipase increased	21/140 (15%)	23	12/137 (8.8%)	13
Nervous system disorders
Headache	7/140 (5%)	8	4/137 (2.9%)	8
Renal and urinary disorders
Renal impairment	7/140 (5%)	7	8/137 (5.8%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Novo Nordisk maintains the right to be informed of any Investigator plans for publication and to review any scientific paper, presentation, communication or other information concerning the investigation described in this protocol. Any such communication must be submitted in writing to the Novo Nordisk trial manager prior to submission for comments. Comments will be given within four weeks from receipt of the planned communication.