SUSTAIN™ 5: Efficacy and Safety of Semaglutide Once-weekly Versus Placebo as add-on to Basal Insulin Alone or Basal Insulin in Combination With Metformin in Subjects With Type 2 Diabetes

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02305381
• Collaborator: (none)
• Enrollment: 397
• Locations: 99
• Arms: 4
• Actual Duration (Months): 11.7
• Patients Per Site: 4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This trial is conducted in Asia, Europe and the United States of America (USA). The aim of the trial is to investigate efficacy and safety of semaglutide once weekly versus placebo as add-on to basal insulin alone or basal insulin in combination with metformin in subjects with type 2 diabetes.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 397 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Semaglutide Once-weekly Versus Placebo as add-on to Basal Insulin Alone or Basal Insulin in Combination With Metformin in Subjects With Type 2 Diabetes
• Actual Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: Nov 21, 2015
• Actual Study Completion Date: Nov 21, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Semaglutide 0.5 mg/Week	Drug: semaglutide; Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background medication.
Experimental: Semaglutide 1.0 mg/Week	Drug: semaglutide; Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background medication.
Placebo Comparator: Semaglutide Placebo 0.5 mg/Week	Drug: placebo; Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background medication.
Placebo Comparator: Semaglutide Placebo 1.0 mg/Week	Drug: placebo; Injected subcutaneously (s.c. under the skin) once-weekly. As add-on to the pre-trial background medication.

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c (Glycosylated Haemoglobin) [Week 0, week 30]

   Estimated mean change from baseline in HbA1c at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.

Secondary Outcome Measures

1. Change in Body Weight [Week 0, week 30]

   Estimated mean change from baseline in body weight at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.

2. Change in Fasting Plasma Glucose (FPG) [week 0, week 30]

   Estimated mean change from baseline in FPG at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.

3. Change in Insulin Dose [week 0, week 30]

   Estimated mean change from baseline in insulin dose at week 30 was measured in terms of ratio to baseline. Responses at week 30 are analysed using an Analysis of covariance model with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward.

4. Change in Systolic and Diastolic Blood Pressure [week 0, week 30]

   Estimated mean change from baseline in systolic and diastolic blood pressure at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.

5. Patient Reported Outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ) [week 0, week 30]

   The DTSQs questionnaire was used to assess subjects' treatment satisfaction and contained 8 components and evaluates the diabetes treatment (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings towards the treatment. The result presented is the 'Treatment Satisfaction' summary score, which is the sum of 6 of the 8 items of the DTSQs questionnaire. Response options range from 6 (best case) to 0 (worst case). Total scores for treatment satisfaction range from 0-36. Higher scores indicate higher satisfaction. The post-baseline responses are analysed using an ANCOVA model with treatment, country and stratification variables (HbA1c level at screening [<= 8.0% or > 8.0%] and use of metformin [yes or no]) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward.

6. HbA1c Below 7.0% (53 mmol/Mol) American Diabetes Association (ADA) Target [After 30 weeks treatment]

   Percentage of subjects with HbA1C below 7.0% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit.

7. HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target [After 30 weeks treatment]

   Percentage of participants with HbA1c below or equal to 6.5% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit.

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 inform consent. For Japan: Male or female, age at least 20 years at the time of signing informed consent - Subjects diagnosed with T2DM (type 2 diabetes mellitus) and on stable diabetes treatment (plus/minus 20 percent change in total daily dose) with basal insulin (minimum of 0.25 IU/kg/day and/or 20 IU/day of: insulin glargine, insulin detemir, insulin degludec and/or NPH insulin) alone or in combination with metformin (minimum of 1500 mg/day or maximal tolerable dose) for 90 days prior to screening - HbA1c (glycosylated haemoglobin) 7.0 - 10.0 percent (53 - 86 mmol/mol) both inclusive Exclusion Criteria: - Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method throughout the trial including the 5 weeks follow-up period (adequate contraceptive measures as required by local regulation or practice). Germany: Only highly effective methods of birth control are accepted (ie one that results in less than 1% per year failure rate when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine device), or sexual abstinence or vasectomised partner. Japan: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives - Treatment with any glucose lowering agents other than stated in the inclusion criteria in a period of 90 days before screening. An exception is short-term treatment (7 days or less in total) with bolus insulin in connection with intercurrent illness - Experienced more than 3 episodes of severe hypoglycaemia within 6 months prior to screening, and/or hypoglycaemia unawareness - History of pancreatitis (acute or chronic) - Screening calcitonin value above or equal to 50 ng/L (pg/mL) - Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome 2 (MEN 2) - Severe renal impairment defined as eGFR (estimated glomerular filtration rate) below 30 mL/min/1.73 m^2 per Modification of Diet in Renal Disease (MDRD) formula (4 variable version) - Acute coronary or cerebrovascular event within 90 days before randomisation - Heart failure, New York Heart Association (NYHA) Class IV

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Phoenix	Arizona	United States	85018
2	Novo Nordisk Investigational Site	Anaheim	California	United States	92801
3	Novo Nordisk Investigational Site	Fresno	California	United States	93720
4	Novo Nordisk Investigational Site	Lomita	California	United States	90717
5	Novo Nordisk Investigational Site	Los Angeles	California	United States	90057-3550
6	Novo Nordisk Investigational Site	Northridge	California	United States	91325
7	Novo Nordisk Investigational Site	Poway	California	United States	92064
8	Novo Nordisk Investigational Site	Riverside	California	United States	92506
9	Novo Nordisk Investigational Site	Roseville	California	United States	95661
10	Novo Nordisk Investigational Site	San Ramon	California	United States	94583
11	Novo Nordisk Investigational Site	Van Nuys	California	United States	91405
12	Novo Nordisk Investigational Site	Walnut Creek	California	United States	94598
13	Novo Nordisk Investigational Site	Waterbury	Connecticut	United States	06708
14	Novo Nordisk Investigational Site	Bradenton	Florida	United States	34201
15	Novo Nordisk Investigational Site	Fleming Island	Florida	United States	32003
16	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32204
17	Novo Nordisk Investigational Site	Port Charlotte	Florida	United States	33952
18	Novo Nordisk Investigational Site	Spring Hill	Florida	United States	34609
19	Novo Nordisk Investigational Site	Tampa	Florida	United States	33634
20	Novo Nordisk Investigational Site	Roswell	Georgia	United States	30076
21	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60607
22	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60611
23	Novo Nordisk Investigational Site	Gillespie	Illinois	United States	62033
24	Novo Nordisk Investigational Site	Skokie	Illinois	United States	60077
25	Novo Nordisk Investigational Site	Avon	Indiana	United States	46123
26	Novo Nordisk Investigational Site	Greenfield	Indiana	United States	46140
27	Novo Nordisk Investigational Site	Indianapolis	Indiana	United States	46254
28	Novo Nordisk Investigational Site	Muncie	Indiana	United States	47304
29	Novo Nordisk Investigational Site	Council Bluffs	Iowa	United States	51501
30	Novo Nordisk Investigational Site	Overland Park	Kansas	United States	66209
31	Novo Nordisk Investigational Site	Topeka	Kansas	United States	66606
32	Novo Nordisk Investigational Site	Lexington	Kentucky	United States	40503
33	Novo Nordisk Investigational Site	Paducah	Kentucky	United States	42003
34	Novo Nordisk Investigational Site	Metairie	Louisiana	United States	70002
35	Novo Nordisk Investigational Site	Rockville	Maryland	United States	20852
36	Novo Nordisk Investigational Site	Waltham	Massachusetts	United States	02453
37	Novo Nordisk Investigational Site	Ann Arbor	Michigan	United States	48106
38	Novo Nordisk Investigational Site	Flint	Michigan	United States	48532
39	Novo Nordisk Investigational Site	Kalamazoo	Michigan	United States	49009
40	Novo Nordisk Investigational Site	Jackson	Mississippi	United States	39209
41	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89103
42	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89128
43	Novo Nordisk Investigational Site	Teaneck	New Jersey	United States	07666
44	Novo Nordisk Investigational Site	Albuquerque	New Mexico	United States	87102
45	Novo Nordisk Investigational Site	West Seneca	New York	United States	14224
46	Novo Nordisk Investigational Site	Cincinnati	Ohio	United States	45245
47	Novo Nordisk Investigational Site	Cincinnati	Ohio	United States	45246
48	Novo Nordisk Investigational Site	Cincinnati	Ohio	United States	45255
49	Novo Nordisk Investigational Site	Dayton	Ohio	United States	45439
50	Novo Nordisk Investigational Site	Kettering	Ohio	United States	45429
51	Novo Nordisk Investigational Site	Oklahoma City	Oklahoma	United States	73162-4704
52	Novo Nordisk Investigational Site	Yukon	Oklahoma	United States	73099
53	Novo Nordisk Investigational Site	Levittown	Pennsylvania	United States	19056-2404
54	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19114
55	Novo Nordisk Investigational Site	Athens	Tennessee	United States	37303
56	Novo Nordisk Investigational Site	Bristol	Tennessee	United States	37620-7352
57	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37411
58	Novo Nordisk Investigational Site	Kingsport	Tennessee	United States	37660
59	Novo Nordisk Investigational Site	Amarillo	Texas	United States	79106
60	Novo Nordisk Investigational Site	Dallas	Texas	United States	75251
61	Novo Nordisk Investigational Site	Dallas	Texas	United States	75390-9302
62	Novo Nordisk Investigational Site	Fort Worth	Texas	United States	76132
63	Novo Nordisk Investigational Site	Houston	Texas	United States	77008
64	Novo Nordisk Investigational Site	Hurst	Texas	United States	76054
65	Novo Nordisk Investigational Site	Katy	Texas	United States	77450
66	Novo Nordisk Investigational Site	Mesquite	Texas	United States	75149
67	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78224
68	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77478
69	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77479
70	Novo Nordisk Investigational Site	Bountiful	Utah	United States	84010
71	Novo Nordisk Investigational Site	Richmond	Virginia	United States	23219
72	Novo Nordisk Investigational Site	Kenosha	Wisconsin	United States	53144
73	Novo Nordisk Investigational Site	Essen		Germany	45219
74	Novo Nordisk Investigational Site	Falkensee		Germany	14612
75	Novo Nordisk Investigational Site	Friedrichsthal		Germany	66299
76	Novo Nordisk Investigational Site	Hamburg		Germany	21073
77	Novo Nordisk Investigational Site	Hamburg		Germany	22587
78	Novo Nordisk Investigational Site	Hamburg		Germany	22607
79	Novo Nordisk Investigational Site	Hohenmölsen		Germany	06679
80	Novo Nordisk Investigational Site	Münster		Germany	48145
81	Novo Nordisk Investigational Site	Rehlingen-Siersburg		Germany	66780
82	Novo Nordisk Investigational Site	Saint Ingbert-Oberwürzbach		Germany	66386
83	Novo Nordisk Investigational Site	Stuttgart		Germany	70378
84	Novo Nordisk Investigational Site	Sulzbach-Rosenberg		Germany	92237
85	Novo Nordisk Investigational Site	Ibaraki		Japan	311-0113
86	Novo Nordisk Investigational Site	Kashiwara-shi, Osaka		Japan	582-0005
87	Novo Nordisk Investigational Site	Kumamoto-shi, Kumamoto		Japan	860-0811
88	Novo Nordisk Investigational Site	Miyazaki		Japan	880-0034
89	Novo Nordisk Investigational Site	Osaka		Japan	569-1045
90	Novo Nordisk Investigational Site	Tokyo		Japan	103-0027
91	Novo Nordisk Investigational Site	Manati		Puerto Rico	00674
92	Novo Nordisk Investigational Site	Belgrade		Serbia	11000
93	Novo Nordisk Investigational Site	Kragujevac		Serbia	34000
94	Novo Nordisk Investigational Site	Novi Sad		Serbia	21000
95	Novo Nordisk Investigational Site	Bratislava		Slovakia	833 05
96	Novo Nordisk Investigational Site	Kosice		Slovakia	040 01
97	Novo Nordisk Investigational Site	Levice		Slovakia	93401
98	Novo Nordisk Investigational Site	Lucenec		Slovakia	984 01
99	Novo Nordisk Investigational Site	Presov		Slovakia	080 01

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

• Rodbard HW, Bellary S, Hramiak I, Seino Y, Silver R, Damgaard LH, Nayak G, Zacho J, Aroda VR. GREATER COMBINED REDUCTIONS IN HbA(1C) ≥1.0% AND WEIGHT ≥5.0% WITH SEMAGLUTIDE VERSUS COMPARATORS IN TYPE 2 DIABETES. Endocr Pract. 2019 Jun;25(6):589-597. doi: 10.4158/EP-2018-0444. Epub 2019 Mar 13.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT02305381
• Other Study ID Numbers: NN9535-3627; 2013-004502-26; U1111-1149-3738; JapicCTI-142729
• First Posted: Dec 2, 2014
• Last Update Posted: Jun 11, 2019
• Last Verified: May 1, 2019

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 90 sites in 5 countries, as follows: Germany: 10 sites; Japan: 6 sites; Serbia: 4 sites; Slovakia: 5 sites; United States: 65.

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg subcutaneous (sc) injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30.Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
Period Title: Overall Study
STARTED	132	132	133
Exposed	132	131	133
Premature Discontinuation of Treatment	14	16	13
COMPLETED	127	127	126
NOT COMPLETED	5	5	7

Baseline Characteristics

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo	Total
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Total of all reporting groups
Overall Participants	132	131	133	396
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.1 (10.3)	58.5 (9.0)	58.8 (10.9)	58.8 (10.1)
Age, Customized (participants) [Number]
Adults (18-64 years)	93 70.5%	102 77.9%	86 64.7%	281 71%
From 65-84 years	39 29.5%	29 22.1%	46 34.6%	114 28.8%
85 years and over	0 0%	0 0%	1 0.8%	1 0.3%
Sex: Female, Male (Count of Participants)
Female	58 43.9%	54 41.2%	62 46.6%	174 43.9%
Male	74 56.1%	77 58.8%	71 53.4%	222 56.1%
Glycosylated haemoglobin (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.36 (0.83)	8.31 (0.82)	8.42 (0.88)	8.37 (0.84)
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	92.74 (19.57)	92.49 (22.23)	89.88 (21.06)	91.70 (20.97)
Fasting plasma glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	161.0 (62.38)	152.5 (50.91)	154.1 (46.66)	155.9 (53.68)
Insulin dose (international unit) [Median (Full Range) ]
Median (Full Range) [international unit]	35.00	36.00	36.00	36.00
Diastolic Blood Pressure (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	78.89 (9.72)	78.73 (9.98)	79.35 (9.71)	78.99 (9.79)
Systolic Blood Pressure (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	134.87 (15.00)	134.40 (16.32)	134.99 (16.68)	134.76 (15.98)
Diabetes Treatment Satisfaction Questionnaire (scores on scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on scale]	28.86 (6.35)	28.62 (6.45)	27.54 (6.55)	28.34 (6.46)

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c (Glycosylated Haemoglobin)
Description	Estimated mean change from baseline in HbA1c at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.
Time Frame	Week 0, week 30

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects who had received at least 1 dose of randomised semaglutide or placebo.

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
Measure Participants	132	131	133
Least Squares Mean (Standard Error) [percentage of glycosylated hemoglobin]	-1.45 (0.09)	-1.85 (0.09)	-0.09 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Semaglutide 1.0 mg, Placebo
	Comments	Hierarchical testing was performed as per sequence listed below:Change in HbA1c: semaglutide 1.0 mg vs placebo. Change in HbA1c: semaglutide 0.5 mg vs placebo. Change in body weight: semaglutide 1.0 mg vs placebo. Change in body weight: semaglutide 0.5 mg vs placebo. Analysis was performed using MMRM with treatment, country and stratification variable (HbA1c at screening [≤8.0% or >8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate
	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	-1.75
	Confidence Interval	(2-Sided) 95%; -2.01 to -1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Superiority for change in HbA1c was claimed if the upper limit of the 2-sided 95% CI for the estimated difference was below 0%.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Semaglutide 0.5 mg, Placebo
	Comments	Hierarchical testing was performed as per sequence listed below:Change in HbA1c: semaglutide 1.0 mg vs placebo. Change in HbA1c: semaglutide 0.5 mg vs placebo. Change in body weight: semaglutide 1.0 mg vs placebo. Change in body weight: semaglutide 0.5 mg vs placebo. Analysis was performed using MMRM with treatment, country and stratification variable (HbA1c at screening [≤8.0% or >8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate
	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	-1.35
	Confidence Interval	(2-Sided) 95%; -1.61 to -1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Superiority for change in HbA1c was claimed if the upper limit of the 2-sided 95% CI for the estimated difference was below 0%.

2. Secondary Outcome

Title	Change in Body Weight
Description	Estimated mean change from baseline in body weight at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.
Time Frame	Week 0, week 30

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
Measure Participants	132	131	133
Least Squares Mean (Standard Error) [kg]	-3.67 (0.36)	-6.42 (0.36)	-1.36 (0.37)

3. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG)
Description	Estimated mean change from baseline in FPG at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.
Time Frame	week 0, week 30

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
Measure Participants	132	131	133
Least Squares Mean (Standard Error) [mg/dL]	-29.14 (3.74)	-42.38 (3.76)	-8.51 (4.02)

4. Secondary Outcome

Title	Change in Insulin Dose
Description	Estimated mean change from baseline in insulin dose at week 30 was measured in terms of ratio to baseline. Responses at week 30 are analysed using an Analysis of covariance model with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward.
Time Frame	week 0, week 30

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
Measure Participants	132	131	133
Least Squares Mean (Standard Error) [ratio]	0.90 (0.01)	0.85 (0.01)	0.96 (0.01)

5. Secondary Outcome

Title	Change in Systolic and Diastolic Blood Pressure
Description	Estimated mean change from baseline in systolic and diastolic blood pressure at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements.
Time Frame	week 0, week 30

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
Measure Participants	132	131	133
Diastolic blood pressure	-1.84 (0.73)	-1.50 (0.74)	-2.17 (0.79)
Systolic blood pressure	-4.29 (1.26)	-7.27 (1.27)	-0.99 (1.34)

6. Secondary Outcome

Title	Patient Reported Outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ)
Description	The DTSQs questionnaire was used to assess subjects' treatment satisfaction and contained 8 components and evaluates the diabetes treatment (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings towards the treatment. The result presented is the 'Treatment Satisfaction' summary score, which is the sum of 6 of the 8 items of the DTSQs questionnaire. Response options range from 6 (best case) to 0 (worst case). Total scores for treatment satisfaction range from 0-36. Higher scores indicate higher satisfaction. The post-baseline responses are analysed using an ANCOVA model with treatment, country and stratification variables (HbA1c level at screening [<= 8.0% or > 8.0%] and use of metformin [yes or no]) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward.
Time Frame	week 0, week 30

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
Measure Participants	132	131	133
Least Squares Mean (Standard Error) [scores on a scale]	2.73 (0.46)	3.47 (0.46)	1.25 (0.50)

7. Secondary Outcome

Title	HbA1c Below 7.0% (53 mmol/Mol) American Diabetes Association (ADA) Target
Description	Percentage of subjects with HbA1C below 7.0% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit.
Time Frame	After 30 weeks treatment

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
Measure Participants	132	131	133
Number [percentage of subjects]	60.6	78.6	10.5

8. Secondary Outcome

Title	HbA1c Below or Equal to 6.5% (48 mmol/Mol) American Association of Clinical Endocrinologists (AACE) Target
Description	Percentage of participants with HbA1c below or equal to 6.5% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit.
Time Frame	After 30 weeks treatment

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.	Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
Measure Participants	132	131	133
Number [percentage of subjects]	40.9	61.1	4.5

Adverse Events

Time Frame	From the first dose of trial product until the end of the post-treatment follow-up period.The follow-up visit was scheduled to take place 5 weeks after the date of last dose of trial product with a visit window of +7 days (maximum 36 weeks).
Adverse Event Reporting Description	A treatment-emergent adverse event (TEAE) was defined as an AE that had onset date (or increased in severity) during the 'on-treatment' observation period.
Arm/Group Title	Semaglutide 0.5 mg		Semaglutide 1.0 mg		Placebo
Arm/Group Description	Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.		Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30. Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.		Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks. Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.
All Cause Mortality
	Semaglutide 0.5 mg		Semaglutide 1.0 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Semaglutide 0.5 mg		Semaglutide 1.0 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/132 (6.1%)		12/131 (9.2%)		9/133 (6.8%)
Blood and lymphatic system disorders
Anaemia	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Cardiac disorders
Acute coronary syndrome	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Cardiac failure	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Coronary artery disease	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Eye disorders
Cataract	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Gastrointestinal disorders
Gastrooesophageal reflux disease	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
General disorders
Pyrexia	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Immune system disorders
Drug hypersensitivity	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Infections and infestations
Bronchitis	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Clostridium difficile colitis	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Diverticulitis	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Meningitis aseptic	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Pneumonia	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Pyelonephritis	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Pyelonephritis acute	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Sinusitis	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Injury, poisoning and procedural complications
Procedural pain	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Investigations
Blood pressure increased	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Weight decreased	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Hypoglycaemia	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Lumbar spinal stenosis	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Spondylolisthesis	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Nervous system disorders
Carotid artery stenosis	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Hypoglycaemic unconsciousness	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Ischaemic stroke	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Psychiatric disorders
Depression	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Schizophrenia	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Surgical and medical procedures
Carotid endarterectomy	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Coronary arterial stent insertion	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Coronary artery bypass	0/132 (0%)	0	1/131 (0.8%)	1	1/133 (0.8%)	1
Peripheral artery angioplasty	1/132 (0.8%)	1	0/131 (0%)	0	0/133 (0%)	0
Peripheral artery stent insertion	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Vascular disorders
Femoral artery occlusion	0/132 (0%)	0	0/131 (0%)	0	1/133 (0.8%)	1
Peripheral arterial occlusive disease	0/132 (0%)	0	1/131 (0.8%)	1	0/133 (0%)	0
Other (Not Including Serious) Adverse Events
	Semaglutide 0.5 mg		Semaglutide 1.0 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/132 (39.4%)		54/131 (41.2%)		34/133 (25.6%)
Gastrointestinal disorders
Diarrhoea	6/132 (4.5%)	6	9/131 (6.9%)	9	2/133 (1.5%)	2
Nausea	15/132 (11.4%)	21	22/131 (16.8%)	23	6/133 (4.5%)	6
Vomiting	8/132 (6.1%)	9	15/131 (11.5%)	17	4/133 (3%)	4
Infections and infestations
Nasopharyngitis	11/132 (8.3%)	14	6/131 (4.6%)	6	14/133 (10.5%)	16
Upper respiratory tract infection	8/132 (6.1%)	10	1/131 (0.8%)	1	4/133 (3%)	4
Urinary tract infection	2/132 (1.5%)	3	4/131 (3.1%)	5	8/133 (6%)	11
Investigations
Lipase increased	12/132 (9.1%)	15	7/131 (5.3%)	7	4/133 (3%)	4
Metabolism and nutrition disorders
Decreased appetite	5/132 (3.8%)	5	7/131 (5.3%)	7	1/133 (0.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. 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.