Efficacy and Safety of Liraglutide in Combination With Insulin Therapy Compared to Insulin Alone in Japanese Subjects With Type 2 Diabetes

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01572740
• Collaborator: (none)
• Enrollment: 257
• Locations: 23
• Arms: 2
• Actual Duration (Months): 11.7
• Patients Per Site: 11.2
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This trial is conducted in Asia. The purpose of the trial is to investigate the efficacy and safety of liraglutide in combination with insulin therapy compared to insulin alone in Japanese subjects with type 2 diabetes mellitus. Subjects will remain on their pre-trial insulin therapy.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 257 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A 36-week, Randomised, Multi-centre, Double-blind, Parallel Group Trial to Investigate the Efficacy and Safety of Liraglutide in Combination With Insulin Therapy Compared to Insulin Monotherapy in Japanese Subjects With Type 2 Diabetes Mellitus
• Actual Study Start Date: Apr 5, 2012
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Mar 27, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lira+Insulin	Drug: liraglutide; Liraglutide administered subcutaneously (s.c., under the skin) for 36 weeks combined with insulin therapy.; Drug: insulin; All subjects will continue their pre-trial insulin therapy (basal, premixed or basal-bolus regimen) during the trial. Insulin dose is fixed for the first 16 weeks and for the subsequent 20 weeks, insulin dose is individually adjusted.
Placebo Comparator: Placebo+Insulin	Drug: placebo; Liraglutide placebo administered subcutaneously (s.c., under the skin) for 36 weeks combined with insulin therapy.; Drug: insulin; All subjects will continue their pre-trial insulin therapy (basal, premixed or basal-bolus regimen) during the trial. Insulin dose is fixed for the first 16 weeks and for the subsequent 20 weeks, insulin dose is individually adjusted.

Outcome Measures

Primary Outcome Measures

1. Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 16 [Week 0, Week 16]

   Estimated mean change from baseline in HbA1c after 16 Weeks of treatment.

Secondary Outcome Measures

1. Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 36 [Week 0, Week 36]

   Estimated mean change from baseline in HbA1c after 36 Weeks of treatment

2. Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16 [Week 0, Week 16]

   Estimated mean change from baseline in FPG after 16 Weeks of treatment.

3. Change in Fasting Plasma Glucose (FPG) From Baseline to Week 36 [Week 0, Week 36]

   Estimated mean change from baseline in FPG after 36 Weeks of treatment.

4. Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 16 [Week 0, Week 16]

   Estimated mean change from baseline in mean PG of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 16 Weeks of treatment.

5. Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 36 [Week 0, Week 36]

   Estimated mean change from baseline in mean PG of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 36 Weeks of treatment.

6. Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 16 [Week 0, Week 16]

   Estimated mean change from baseline in mean prandial PG increment of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 16 Weeks of treatment.

7. Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 36 [Week 0, Week 36]

   Estimated mean change from baseline in mean prandial PG increment of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 36 Weeks of treatment.

8. Change in Body Weight From Baseline to Week 16 [Week 0, Week 16]

   Estimated mean change in body weight after 16 Weeks of treatment

9. Change in Body Weight From Baseline to Week 36 [Week 0, Week 36]

   Estimated mean change in body weight after 36 Weeks of treatment

10. Number of Adverse Events (AEs) [Week 0 to Week 36 (inclusive)]

    An AE was defined as treatment emergent if the onset date was on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.

11. Number of Confirmed Hypoglycaemic Episodes [Week 0 to week 36 (inclusive)]

    A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and until the last day on randomised treatment. Confirmed hypoglycaemic episode was defined as hypoglycaemic episodes categorised to severe and/or minor hypoglycaemic episodes. Confirmed hypoglycaemia: subject unable to treat himself/herself and/or have a recorded PG < 3.1 mmol/L (56 mg/dL). Minor: PG < 3.1 mmol/L (56 mg/dL).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 2 diabetes mellitus (diagnosed clinically) for at least 6 months

• Current insulin therapy (basal insulin, premixed insulin or basal-bolus regimen) in addition to diet and exercise therapy for at least 12 weeks prior to trial start. Their therapy is stable and fluctuation of total daily insulin dose is within plus/minus 20% for at least 12 weeks prior to trial start and current total daily insulin dose equal to or greater than 10 (I)U/day

• Glycosylated haemoglobin (HbA1c) between 7.5 and 11.0% (both inclusive)

• Body Mass Index (BMI) below 45.0 kg/m^2

Exclusion Criteria:

• Anticipated change in concomitant medication known to interfere significantly with glucose metabolism, such as, but not limited to systemic corticosteroids, beta-antagonists or monoamine oxidase (MAO) inhibitors

• Recurrent severe hypoglycaemia (more than 1 severe hypoglycaemic episode during last 12 months) or hypoglycaemic unawareness as judged by the investigator or hospitalisation for diabetic ketoacidosis during the previous 6 months

• Known proliferative retinopathy or maculopathy requiring treatment according to the investigator

• Treatment with glucagon-like peptide-1 (GLP-1) receptor agonist within 12 weeks prior to screening

• Treatment with any oral antidiabetic drugs (OADs) within 12 weeks prior to screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Chuo-ku, Tokyo		Japan	103 0002
2	Novo Nordisk Investigational Site	Ebina-shi, Kanagawa		Japan	243 0401
3	Novo Nordisk Investigational Site	Ebina-shi		Japan	243 0432
4	Novo Nordisk Investigational Site	Kashiwara-shi, Osaka		Japan	582 0005
5	Novo Nordisk Investigational Site	Katsushika-ku, Tokyo		Japan	125 0054
6	Novo Nordisk Investigational Site	Koriyama-shi, Fukushima		Japan	963 8851
7	Novo Nordisk Investigational Site	Miyazaki-shi		Japan	880 0034
8	Novo Nordisk Investigational Site	Naka-shi, Ibaraki		Japan	311 0113
9	Novo Nordisk Investigational Site	Niigata-shi, Niigata		Japan	950 1104
10	Novo Nordisk Investigational Site	Nishinomiya-shi, Hygo		Japan	662 0971
11	Novo Nordisk Investigational Site	Oita-shi		Japan	870 0039
12	Novo Nordisk Investigational Site	Okawa-shi, Fukuoka		Japan	831 0016
13	Novo Nordisk Investigational Site	Osaka-shi, Osaka		Japan	553 0003
14	Novo Nordisk Investigational Site	Ota-ku, Tokyo		Japan	144 0035
15	Novo Nordisk Investigational Site	Oyama-shi, Tochigi		Japan	323 0022
16	Novo Nordisk Investigational Site	Sapporo-shi, Hokkaido		Japan	060 0062
17	Novo Nordisk Investigational Site	Sapporo-shi, Hokkaido		Japan	062 0007
18	Novo Nordisk Investigational Site	Sendai-shi		Japan	980 0021
19	Novo Nordisk Investigational Site	Shimotsuke-shi, Tochigi		Japan	329 0433
20	Novo Nordisk Investigational Site	Shizuoka-shi		Japan	424 0853
21	Novo Nordisk Investigational Site	Takatsuki-shi, Osaka		Japan	569 1096
22	Novo Nordisk Investigational Site	Tokyo		Japan	187 8510
23	Novo Nordisk Investigational Site	Yokohama-shi		Japan	235 0045

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: NCT01572740
• Other Study ID Numbers: NN2211-3925; U1111-1122-4320; JapicCTI-121802
• First Posted: Apr 6, 2012
• Last Update Posted: Feb 7, 2018
• Last Verified: Jan 1, 2018

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

Study Results

Participant Flow

Recruitment Details	This trial was conducted at 23 sites in Japan.
Pre-assignment Detail	Subjects on pre-trial insulin (basal insulin [intermediate acting human insulin, intermediate acting insulin analogue or long-acting insulin analogue], premixed insulin or basal-bolus regimen) therapy for at least 12 weeks prior to screening.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Period Title: Overall Study
STARTED	127	130
COMPLETED	121	125
NOT COMPLETED	6	5

Baseline Characteristics

Arm/Group Title	Lira + Insulin	Placebo + Insulin	Total
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Total of all reporting groups
Overall Participants	127	130	257
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.3 (11.0)	59.8 (11.3)	60.5 (11.2)
Sex: Female, Male (Count of Participants)
Female	58 45.7%	55 42.3%	113 44%
Male	69 54.3%	75 57.7%	144 56%
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	67.7 (15.2)	65.9 (13.0)	66.8 (14.1)
Fasting Plasma Glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	8.51 (2.42)	8.79 (2.51)	8.65 (2.47)
Glycosylated Haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.8 (0.9)	8.8 (0.9)	8.8 (0.9)

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 16
Description	Estimated mean change from baseline in HbA1c after 16 Weeks of treatment.
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 16 as subject was withdrawn from the trial before sampling for any efficacy data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	127	129
Mean (Standard Error) [percentage of glycosylated haemoglobin]	-1.73 (0.06)	-0.43 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-1.30
	Confidence Interval	() 95%; -1.47 to -1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 36
Description	Estimated mean change from baseline in HbA1c after 36 Weeks of treatment
Time Frame	Week 0, Week 36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 36 as subject was withdrawn from the trial before sampling for any efficacy data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	127	129
Mean (Standard Error) [percentage of glycosylated haemoglobin]	-1.68 (0.06)	-0.88 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-0.81
	Confidence Interval	() 95%; -0.99 to -0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16
Description	Estimated mean change from baseline in FPG after 16 Weeks of treatment.
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 16 as subject was withdrawn from the trial before sampling for any efficacy data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	127	129
Mean (Standard Error) [mmol/L]	-1.31 (0.17)	-0.48 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0006
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-0.83
	Confidence Interval	() 95%; -1.30 to -0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG) From Baseline to Week 36
Description	Estimated mean change from baseline in FPG after 36 Weeks of treatment.
Time Frame	Week 0, Week 36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 36 as subject was withdrawn from the trial before sampling for any efficacy data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	127	129
Mean (Standard Error) [mmol/L]	-1.55 (0.16)	-1.29 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2511
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-0.26
	Confidence Interval	() 95%; -0.70 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 16
Description	Estimated mean change from baseline in mean PG of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 16 Weeks of treatment.
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 9 subjects did not contribute to the statistical analysis at Week 16 due to missing data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	124	124
Mean (Standard Error) [mmol/L]	-2.41 (0.18)	-0.53 (0.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-1.87
	Confidence Interval	() 95%; -2.37 to -1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in Mean Plasma Glucose (PG) of 7-Point Profile From Baseline to Week 36
Description	Estimated mean change from baseline in mean PG of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 36 Weeks of treatment.
Time Frame	Week 0, Week 36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 8 subjects did not contribute to the statistical analysis at Week 36 due to missing data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	124	125
Mean (Standard Error) [mmol/L]	-2.65 (0.16)	-1.37 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-1.28
	Confidence Interval	() 95%; -1.73 to -0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 16
Description	Estimated mean change from baseline in mean prandial PG increment of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 16 Weeks of treatment.
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 9 subjects did not contribute to the statistical analysis at Week 16 due to missing data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	124	124
Mean (Standard Error) [mmol/L]	-1.34 (0.17)	-0.61 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0023
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-0.73
	Confidence Interval	() 95%; -1.20 to -0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change in Mean Prandial PG Increment of 7-Point Profile From Baseline to Week 36
Description	Estimated mean change from baseline in mean prandial PG increment of 7-point profile (7-points were before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner and at bedtime) after 36 Weeks of treatment.
Time Frame	Week 0, Week 36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 13 subjects did not contribute to the statistical analysis at Week 36 due to missing data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	122	122
Mean (Standard Error) [mmol/L]	-1.34 (0.21)	-0.94 (0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1787
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-0.39
	Confidence Interval	() 95%; -0.97 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change in Body Weight From Baseline to Week 16
Description	Estimated mean change in body weight after 16 Weeks of treatment
Time Frame	Week 0, Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 16 as subject was withdrawn from the trial before sampling for any efficacy data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	127	129
Mean (Standard Error) [kg]	-0.42 (0.14)	-0.28 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4806
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-0.14
	Confidence Interval	() 95%; -0.54 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change in Body Weight From Baseline to Week 36
Description	Estimated mean change in body weight after 36 Weeks of treatment
Time Frame	Week 0, Week 36

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects who received at least one dose of trial products. Missing data were imputed using last observation carried forward (LOCF). 1 subject in the placebo group did not contribute to the statistical analysis at Week 36 as subject was withdrawn from the trial before sampling for any efficacy data.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	127	129
Mean (Standard Error) [kg]	0.17 (0.20)	0.52 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lira + Insulin, Placebo + Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2074
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	-0.35
	Confidence Interval	() 95%; -0.91 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Number of Adverse Events (AEs)
Description	An AE was defined as treatment emergent if the onset date was on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.
Time Frame	Week 0 to Week 36 (inclusive)

Outcome Measure Data

Analysis Population Description

Safety analysis set includes all subjects who received at least one dose of the trial products.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	127	130
Adverse Events	449	350
Serious Adverse Events	8	5
Severe Adverse Events	5	1
Moderate Adverse Events	8	14
Mild Adverse Events	436	335

12. Secondary Outcome

Title	Number of Confirmed Hypoglycaemic Episodes
Description	A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and until the last day on randomised treatment. Confirmed hypoglycaemic episode was defined as hypoglycaemic episodes categorised to severe and/or minor hypoglycaemic episodes. Confirmed hypoglycaemia: subject unable to treat himself/herself and/or have a recorded PG < 3.1 mmol/L (56 mg/dL). Minor: PG < 3.1 mmol/L (56 mg/dL).
Time Frame	Week 0 to week 36 (inclusive)

Outcome Measure Data

Analysis Population Description

Safety analysis set includes all subjects who received at least one dose of the trial products.

Arm/Group Title	Lira + Insulin	Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.	Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
Measure Participants	127	130
Number [Episodes/100 years of patient exposure]	146	187

Adverse Events

Time Frame	Adverse events were collected in a timeframe of 36 weeks + 7 days follow up.
Adverse Event Reporting Description	Safety analysis set includes all subjects who received at least one dose of the trial products.
Arm/Group Title	Lira + Insulin		Placebo + Insulin
Arm/Group Description	Liraglutide was administered subcutaneously (s.c., under the skin) once daily (OD) for 36 weeks combined with insulin therapy. The starting dose of the liraglutide was 0.3 mg (50 μL)/day; dose was escalated to 0.6 mg (100 μL)/day and 0.9 mg (150 μL)/day during first 2 weeks; dose was maintained at 0.9 mg (150 μL)/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.		Liraglutide placebo was administered subcutaneously (s.c., under the skin) OD for 36 weeks combined with insulin therapy. The starting dose of the placebo was 50 μL/day; dose was escalated to100 μL/day and 150 μL/day during first 2 weeks; dose was maintained at 150 μL/day for subsequent 34 weeks. All subjects continued their pre-trial insulin therapy (basal: once daily [OD] or twice daily [BID], premixed: OD or BID or basal-bolus regimen [basal: OD or BID and bolus: three times a day]). Insulin dose was not changed for any subject for the first 16 weeks and for the subsequent 20 weeks, insulin dose was individually adjusted.
All Cause Mortality
	Lira + Insulin		Placebo + Insulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lira + Insulin		Placebo + Insulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/127 (4.7%)		4/130 (3.1%)
Cardiac disorders
Acute myocardial infarction	0/127 (0%)	0	1/130 (0.8%)	1
Angina pectoris	1/127 (0.8%)	1	0/130 (0%)	0
Eye disorders
Cataract	1/127 (0.8%)	1	0/130 (0%)	0
Macular fibrosis	1/127 (0.8%)	1	0/130 (0%)	0
Infections and infestations
Pneumonia	0/127 (0%)	0	1/130 (0.8%)	1
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis	1/127 (0.8%)	1	0/130 (0%)	0
Nervous system disorders
Brain stem thrombosis	1/127 (0.8%)	1	0/130 (0%)	0
Carotid artery stenosis	1/127 (0.8%)	1	0/130 (0%)	0
Cerebral infarction	0/127 (0%)	0	1/130 (0.8%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/127 (0%)	0	1/130 (0.8%)	1
Vascular disorders
Hypertension	1/127 (0.8%)	1	0/130 (0%)	0
Other (Not Including Serious) Adverse Events
	Lira + Insulin		Placebo + Insulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/127 (73.2%)		69/130 (53.1%)
Eye disorders
Diabetic retinopathy	9/127 (7.1%)	9	13/130 (10%)	16
Gastrointestinal disorders
Constipation	15/127 (11.8%)	16	2/130 (1.5%)	2
Diarrhoea	15/127 (11.8%)	17	4/130 (3.1%)	4
Dyspepsia	7/127 (5.5%)	9	0/130 (0%)	0
Nausea	14/127 (11%)	16	7/130 (5.4%)	9
Infections and infestations
Gastroenteritis	4/127 (3.1%)	7	7/130 (5.4%)	7
Nasopharyngitis	55/127 (43.3%)	74	40/130 (30.8%)	60
Musculoskeletal and connective tissue disorders
Back pain	6/127 (4.7%)	6	7/130 (5.4%)	7
Nervous system disorders
Headache	8/127 (6.3%)	10	6/130 (4.6%)	6
Vascular disorders
Hypertension	8/127 (6.3%)	8	6/130 (4.6%)	6

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.