onset® 2: Efficacy and Safety of FIAsp Compared to Insulin Aspart in Combination With Insulin Glargine and Metformin in Adults With Type 2 Diabetes

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01819129
• Collaborator: (none)
• Enrollment: 881
• Locations: 144
• Arms: 2
• Actual Duration (Months): 16.4
• Patients Per Site: 6.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This trial is conducted in Asia, Europe and North America. The aim of the trial is to compare FIAsp (faster-acting insulin aspart) to insulin aspart, both in combination with insulin glargine and metformin in adults with type 2 diabetes.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: Faster-acting insulin aspart; Drug: Insulin aspart; Drug: Insulin glargine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 881 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of FIAsp Compared to Insulin Aspart in Combination With Insulin Glargine and Metformin in Adults With Type 2 Diabetes
• Actual Study Start Date: Sep 9, 2013
• Actual Primary Completion Date: Jan 22, 2015
• Actual Study Completion Date: Jan 22, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Faster-acting insulin aspart (FIAsp) Meal time faster-acting insulin aspart is given in combination with once daily insulin glargine and metformin in a basal-bolus regimen. Insulin glargine and metformin treatment are open labelled background medication.	Drug: Faster-acting insulin aspart; Mealtime FIAsp administered subcutaneously (s.c., under the skin). Dose individually adjusted.; Drug: Insulin glargine; Administered s.c. once daily at subjects' pre-trial dose. Subjects will continue their metformin treatment without changing the frequency or dose throughout the trial.
Active Comparator: Insulin aspart Meal time insulin aspart is given in combination with once daily insulin glargine and metformin in a basal-bolus regimen. Insulin glargine and metformin treatment are open labelled background medication.	Drug: Insulin aspart; Mealtime insulin aspart administered subcutaneously (s.c., under the skin). Dose individually adjusted.; Drug: Insulin glargine; Administered s.c. once daily at subjects' pre-trial dose. Subjects will continue their metformin treatment without changing the frequency or dose throughout the trial.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in HbA1c [Week 0, Week 26]

   The primary endpoint was change from baseline in HbA1c after 26 weeks of randomized treatment. For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.

Secondary Outcome Measures

1. Change From Baseline in 2-hour PPG Increment (Meal Test) [Week 0, week 26]

   For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.

2. Number of Treatment Emergent Confirmed Hypoglycaemic Episodes [From Week 0 to Week 26.]

   A hypoglycaemic episode was defined as treatment-emergent if the onset of the episode was on or after the first day of exposure to randomized treatment and no later than 1 day after the last day of randomized treatment. A severe or blood glucose (BG) confirmed hypoglycaemic episode was an episode that was severe according to the American Diabetes Association (ADA) classification (an episode that required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia.

3. Change From Baseline in Body Weight [Week 0, week 26]

   For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.

Eligibility Criteria

Criteria

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

Inclusion Criteria: - Type 2 diabetes (diagnosed clinically) for 6 months or longer at time of screening (visit 1) - Treated with basal insulin for at least 6 months prior to screening (visit 1) - Current once daily treatment with insulin NPH (Neutral Protamine Hagedorn), insulin detemir or glargine for at least 3 months prior to the screening visit (visit 1) - Current treatment with: a. metformin with unchanged dosing for at least 3 months prior to screening (visit 1). The metformin dose must be at least 1000 mg or b. metformin in combination with sulfonylurea (SU) or glinide or DPP-IV (dipeptidyl peptidase-4) inhibitors and/or alpha-glucosidase inhibitors (AGI) with unchanged dosing for at least 3 months prior to screening (visit 1). The metformin dose must be at least 1000 mg

• HbA1c by central laboratory: a. 7.0 - 9.5% (53 - 80 mmol/mol) (both inclusive) in the metformin group at the screening visit (visit 1) or b. 7.0 - 9.0% (53 - 75 mmol/mol) (both inclusive) in the metformin + other OAD (oral antidiabetic drug) (SU, glinide, DDP-IV inhibitors, AGI) combination group at the screening visit (visit 1) - Body mass index (BMI) equal to or below 40.0 kg/m^2 Exclusion Criteria: - Any use of bolus insulin, except short-term use due to intermittent illness (no longer than 14 days consecutive treatment) and not 3 months prior to the screening visit (visit 1) - Use of GLP-1 (glucagon-like peptide-1) agonists and/or TZDs within the last 3 months prior to screening (visit 1) - Recurrent severe hypoglycaemia (more than 1 severe hypoglycaemic event during the last 12 months) or hypoglycaemic unawareness as judged by the Investigator or hospitalisation for diabetic ketoacidosis during the previous 6 months prior to screening (visit 1) -

Cardiovascular disease, within the last 6 months prior to screening (visit 1), defined as:

stroke, decompensated heart failure New York Heart Association (NYHA) class III or IV, myocardial infarction, unstable angina pectoris or coronary arterial bypass graft or angioplasty

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Glendale	Arizona	United States	85306-4652
2	Novo Nordisk Investigational Site	Glendale	Arizona	United States	85308
3	Novo Nordisk Investigational Site	Mesa	Arizona	United States	85213
4	Novo Nordisk Investigational Site	Phoenix	Arizona	United States	85020
5	Novo Nordisk Investigational Site	Tempe	Arizona	United States	85283
6	Novo Nordisk Investigational Site	Anaheim	California	United States	92801
7	Novo Nordisk Investigational Site	Fresno	California	United States	93720
8	Novo Nordisk Investigational Site	Greenbrae	California	United States	94904
9	Novo Nordisk Investigational Site	Lomita	California	United States	90717
10	Novo Nordisk Investigational Site	Northridge	California	United States	91325
11	Novo Nordisk Investigational Site	San Diego	California	United States	92111
12	Novo Nordisk Investigational Site	San Ramon	California	United States	94583
13	Novo Nordisk Investigational Site	Walnut Creek	California	United States	94598
14	Novo Nordisk Investigational Site	Aurora	Colorado	United States	80045
15	Novo Nordisk Investigational Site	Colorado Springs	Colorado	United States	80910
16	Novo Nordisk Investigational Site	Waterbury	Connecticut	United States	06708
17	Novo Nordisk Investigational Site	Boynton Beach	Florida	United States	33472
18	Novo Nordisk Investigational Site	Bradenton	Florida	United States	34201
19	Novo Nordisk Investigational Site	Cooper City	Florida	United States	33024
20	Novo Nordisk Investigational Site	Fort Lauderdale	Florida	United States	33316
21	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32205
22	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32216
23	Novo Nordisk Investigational Site	Miami	Florida	United States	33144
24	Novo Nordisk Investigational Site	Miami	Florida	United States	33173
25	Novo Nordisk Investigational Site	Pembroke Pines	Florida	United States	33027
26	Novo Nordisk Investigational Site	Plantation	Florida	United States	33324
27	Novo Nordisk Investigational Site	Tampa	Florida	United States	33603
28	Novo Nordisk Investigational Site	Atlanta	Georgia	United States	30308-2253
29	Novo Nordisk Investigational Site	Atlanta	Georgia	United States	30328
30	Novo Nordisk Investigational Site	Decatur	Georgia	United States	30033
31	Novo Nordisk Investigational Site	Roswell	Georgia	United States	30076
32	Novo Nordisk Investigational Site	Avon	Illinois	United States	46123
33	Novo Nordisk Investigational Site	Peoria	Illinois	United States	61602
34	Novo Nordisk Investigational Site	Indianapolis	Indiana	United States	46254
35	Novo Nordisk Investigational Site	Muncie	Indiana	United States	47304
36	Novo Nordisk Investigational Site	Topeka	Kansas	United States	66606
37	Novo Nordisk Investigational Site	Louisville	Kentucky	United States	40206
38	Novo Nordisk Investigational Site	Madisonville	Kentucky	United States	42431-1661
39	Novo Nordisk Investigational Site	Paducah	Kentucky	United States	42003
40	Novo Nordisk Investigational Site	Monroe	Louisiana	United States	71203
41	Novo Nordisk Investigational Site	Buckley	Michigan	United States	49620
42	Novo Nordisk Investigational Site	Detroit	Michigan	United States	48201
43	Novo Nordisk Investigational Site	Troy	Michigan	United States	48085-5524
44	Novo Nordisk Investigational Site	Chesterfield	Missouri	United States	63017
45	Novo Nordisk Investigational Site	Jefferson City	Missouri	United States	65109
46	Novo Nordisk Investigational Site	Saint Louis	Missouri	United States	63141
47	Novo Nordisk Investigational Site	Butte	Montana	United States	59701
48	Novo Nordisk Investigational Site	Elkhorn	Nebraska	United States	68022
49	Novo Nordisk Investigational Site	Omaha	Nebraska	United States	68105
50	Novo Nordisk Investigational Site	Omaha	Nebraska	United States	68198-3020
51	Novo Nordisk Investigational Site	Toms River	New Jersey	United States	08755-8050
52	Novo Nordisk Investigational Site	Mineola	New York	United States	11501
53	Novo Nordisk Investigational Site	New Windsor	New York	United States	12553
54	Novo Nordisk Investigational Site	North Massapequa	New York	United States	11758-1802
55	Novo Nordisk Investigational Site	Northport	New York	United States	11768
56	Novo Nordisk Investigational Site	Hickory	North Carolina	United States	28601
57	Novo Nordisk Investigational Site	Wilmington	North Carolina	United States	28401
58	Novo Nordisk Investigational Site	Carlisle	Ohio	United States	45005
59	Novo Nordisk Investigational Site	Cleveland	Ohio	United States	44122
60	Novo Nordisk Investigational Site	Dayton	Ohio	United States	45439
61	Novo Nordisk Investigational Site	Franklin	Ohio	United States	45005
62	Novo Nordisk Investigational Site	Mason	Ohio	United States	45040-6815
63	Novo Nordisk Investigational Site	East Providence	Rhode Island	United States	02914
64	Novo Nordisk Investigational Site	Gaffney	South Carolina	United States	29341
65	Novo Nordisk Investigational Site	Chattanooga	Tennessee	United States	37404-1192
66	Novo Nordisk Investigational Site	Kingsport	Tennessee	United States	37660
67	Novo Nordisk Investigational Site	Spring Hill	Tennessee	United States	37174
68	Novo Nordisk Investigational Site	Tullahoma	Tennessee	United States	37388
69	Novo Nordisk Investigational Site	Dallas	Texas	United States	75230
70	Novo Nordisk Investigational Site	Dallas	Texas	United States	75251
71	Novo Nordisk Investigational Site	Hurst	Texas	United States	76054
72	Novo Nordisk Investigational Site	Plano	Texas	United States	75075
73	Novo Nordisk Investigational Site	Murray	Utah	United States	84123
74	Novo Nordisk Investigational Site	Midlothian	Virginia	United States	23114
75	Novo Nordisk Investigational Site	Port Orchard	Washington	United States	98366
76	Novo Nordisk Investigational Site	Kenosha	Wisconsin	United States	53144
77	Novo Nordisk Investigational Site	Milwaukee	Wisconsin	United States	53209
78	Novo Nordisk Investigational Site	Edmonton	Alberta	Canada	T5J 3N4
79	Novo Nordisk Investigational Site	Surrey	British Columbia	Canada	V3S 2N6
80	Novo Nordisk Investigational Site	Mount Pearl	Newfoundland and Labrador	Canada	A1N 1W7
81	Novo Nordisk Investigational Site	St. John's	Newfoundland and Labrador	Canada	A1A 3R5
82	Novo Nordisk Investigational Site	Hamilton	Ontario	Canada	L8M 1K7
83	Novo Nordisk Investigational Site	Thunder Bay	Ontario	Canada	P7B 7C7
84	Novo Nordisk Investigational Site	Waterloo	Ontario	Canada	N2J 1C4
85	Novo Nordisk Investigational Site	Mirabel	Quebec	Canada	J7J 2K8
86	Novo Nordisk Investigational Site	Montreal	Quebec	Canada	H1Y 3L1
87	Novo Nordisk Investigational Site	Montreal	Quebec	Canada	H2R 1V6
88	Novo Nordisk Investigational Site	St. Romuald	Quebec	Canada	G6W 5M6
89	Novo Nordisk Investigational Site	Quebec		Canada	G1G 3Y8
90	Novo Nordisk Investigational Site	Quebec		Canada	G1N 4V3
91	Novo Nordisk Investigational Site	Cakovec		Croatia	40000
92	Novo Nordisk Investigational Site	Karlovac		Croatia	47000
93	Novo Nordisk Investigational Site	Osijek		Croatia	31 000
94	Novo Nordisk Investigational Site	Slavonski Brod		Croatia	35 000
95	Novo Nordisk Investigational Site	Split		Croatia	21 000
96	Novo Nordisk Investigational Site	Varazdin		Croatia	42 000
97	Novo Nordisk Investigational Site	Zagreb		Croatia	10 000
98	Novo Nordisk Investigational Site	Zagreb		Croatia	10000
99	Novo Nordisk Investigational Site	Hyderabad	Andhra Pradesh	India	500082
100	Novo Nordisk Investigational Site	Indore	Madhya Pradesh	India	452010
101	Novo Nordisk Investigational Site	Mumbai	Maharashtra	India	400008
102	Novo Nordisk Investigational Site	Mumbai	Maharashtra	India	400012
103	Novo Nordisk Investigational Site	Mumbai	Maharashtra	India	400058
104	Novo Nordisk Investigational Site	Pune	Maharashtra	India	411004
105	Novo Nordisk Investigational Site	Pune	Maharashtra	India	411040
106	Novo Nordisk Investigational Site	Delhi	New Delhi	India	110002
107	Novo Nordisk Investigational Site	Bhubaneswar	Orissa	India	751019
108	Novo Nordisk Investigational Site	Jaipur	Rajasthan	India	302006
109	Novo Nordisk Investigational Site	Beer Sheva		Israel	84101
110	Novo Nordisk Investigational Site	Haifa		Israel	35152
111	Novo Nordisk Investigational Site	Jerusalem		Israel	91120
112	Novo Nordisk Investigational Site	Kfar Saba		Israel	44281
113	Novo Nordisk Investigational Site	Rehovot		Israel	76100
114	Novo Nordisk Investigational Site	Rishon Le Zion		Israel	75650
115	Novo Nordisk Investigational Site	Ponce		Puerto Rico	00717
116	Novo Nordisk Investigational Site	Kursk		Russian Federation	305035
117	Novo Nordisk Investigational Site	Moscow		Russian Federation	117036
118	Novo Nordisk Investigational Site	Moscow		Russian Federation	119435
119	Novo Nordisk Investigational Site	Moscow		Russian Federation	127644
120	Novo Nordisk Investigational Site	Penza		Russian Federation	440026
121	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	191119
122	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	194291
123	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	194358
124	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	195257
125	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	199034
126	Novo Nordisk Investigational Site	Saint-Petesburg		Russian Federation	195257
127	Novo Nordisk Investigational Site	Stavropol		Russian Federation	355035
128	Novo Nordisk Investigational Site	Belgrade		Serbia	11000
129	Novo Nordisk Investigational Site	Nis		Serbia	18000
130	Novo Nordisk Investigational Site	Zajecar		Serbia	19000
131	Novo Nordisk Investigational Site	Bratislava		Slovakia	821 02
132	Novo Nordisk Investigational Site	Bratislava		Slovakia	851 01
133	Novo Nordisk Investigational Site	Lucenec		Slovakia	984 01
134	Novo Nordisk Investigational Site	Trnava		Slovakia	91701
135	Novo Nordisk Investigational Site	Zilina		Slovakia	01001
136	Novo Nordisk Investigational Site	Epworth		United Kingdom	DN9 1EP
137	Novo Nordisk Investigational Site	Hull		United Kingdom	HU3 2RW
138	Novo Nordisk Investigational Site	Northampton		United Kingdom	NN1 5BD
139	Novo Nordisk Investigational Site	Northwood		United Kingdom	HA6 2RN
140	Novo Nordisk Investigational Site	Norwich		United Kingdom	NR4 7TJ
141	Novo Nordisk Investigational Site	Nuneaton		United Kingdom	CV10 7DJ
142	Novo Nordisk Investigational Site	Sidcup		United Kingdom	DA14 6LT
143	Novo Nordisk Investigational Site	Stoke on Trent		United Kingdom	ST4 6QG
144	Novo Nordisk Investigational Site	Wrexham		United Kingdom	LL13 7TD

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: NCT01819129
• Other Study ID Numbers: NN1218-3853; 2010-024051-93; U1111-1118-2509; CTRI/2014/01/004285
• First Posted: Mar 27, 2013
• Last Update Posted: Jan 30, 2019
• Last Verified: Jan 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination

Study Results

Participant Flow

Recruitment Details	Out of 150 sites, which were selected for recruitment, 128 sites in 9 countries enrolled subjects in the run-in period, of which 123 sites later assigned subjects to randomized treatment: Canada:9 sites; Croatia:6 sites; India:6 sites; Israel:6 sites; Russia:12 sites; Serbia:9 sites; Slovakia:5 sites; United Kingdom:7 sites; United States:63 sites.
Pre-assignment Detail	The trial included an 8-week run-in period and a 26-week treatment period. During the run-in period, the subjects received insulin glargine along with metformin. In total, 881 subjects entered the run-in period, of these 192 subjects were run-in failures. Hence, 689 subjects entered the 26-week treatment period.

Arm/Group Title	Faster Aspart	NovoRapid
Arm/Group Description	At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily subcutaneous (sc) injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime self-measured plasma glucose (SMPG) on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Period Title: Overall Study
STARTED	345	344
Exposed	341	341
COMPLETED	301	305
NOT COMPLETED	44	39

Baseline Characteristics

Arm/Group Title	Faster Aspart	NovoRapid	Total
Arm/Group Description	At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	Total of all reporting groups
Overall Participants	345	344	689
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	241 69.9%	248 72.1%	489 71%
>=65 years	104 30.1%	96 27.9%	200 29%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.6 (9.3)	59.4 (9.6)	59.5 (9.4)
Sex: Female, Male (Count of Participants)
Female	182 52.8%	171 49.7%	353 51.2%
Male	163 47.2%	173 50.3%	336 48.8%
Glycosylated haemoglobin A1c (HbA1c) (Percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of glycosylated haemoglobin]	7.96 (0.68)	7.89 (0.71)	7.92 (0.70)
Body Weight (Kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg]	89.0 (16.9)	88.3 (16.7)	88.7 (16.8)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in HbA1c
Description	The primary endpoint was change from baseline in HbA1c after 26 weeks of randomized treatment. For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
Time Frame	Week 0, Week 26

Outcome Measure Data

Analysis Population Description

The analysis of this efficacy endpoint was based on the full analysis set (FAS). FAS included all randomized subjects. The statistical evaluation of the FAS was to follow the intention-to-treat (ITT) principle and subjects contributed to the evaluation 'as randomized'.

Arm/Group Title	Faster Aspart	NovoRapid
Arm/Group Description	At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Measure Participants	345	344
Baseline (week 0)	7.96 (0.68)	7.89 (0.71)
Week 26	6.63 (0.88)	6.59 (0.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faster Aspart, NovoRapid
	Comments	Change from baseline in HbA1c is analysed using a mixed-effect model for repeated measurements including changes from baseline in HbA1c at visit 14, 18, 22, 26, 30 and 36. The model includes treatment, region and continuous glucose monitoring (CGM) strata as fixed effects, subject as random effect, HbA1c at baseline as covariate and interaction between all fixed effects and visit, and between the covariate and visit.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The assessment was done by comparing the difference of faster aspart vs. NovoRapid®/NovoLog® in change from baseline in HbA1c after 26 weeks of randomized treatment to a non-inferiority limit of 0.4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated parameter i.e mean difference is the estimated treatment difference for Faster aspart vs. NovoRapid (Faster aspart - NovoRapid).

2. Secondary Outcome

Title	Change From Baseline in 2-hour PPG Increment (Meal Test)
Description	For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

This endpoint was summarized using the Full Analysis Set (FAS). FAS included all randomized subjects.

Arm/Group Title	Faster Aspart	NovoRapid
Arm/Group Description	At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Measure Participants	345	344
Baseline (week 0)	7.57 (3.19)	7.34 (3.12)
Week 26	4.55 (3.13)	4.9 (3.36)

3. Secondary Outcome

Title	Number of Treatment Emergent 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 randomized treatment and no later than 1 day after the last day of randomized treatment. A severe or blood glucose (BG) confirmed hypoglycaemic episode was an episode that was severe according to the American Diabetes Association (ADA) classification (an episode that required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia.
Time Frame	From Week 0 to Week 26.

Outcome Measure Data

Analysis Population Description

This endpoint was summarized using the safety analysis set. Safety analysis set included all subjects receiving at least one dose of the test product or comparator. Subjects in the safety analysis set contributed to the evaluation 'as treated'.

Arm/Group Title	Faster Aspart	NovoRapid
Arm/Group Description	At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Measure Participants	341	341
Number [Number of episodes]	2857	2692

4. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	For this endpoint baseline (week 0) and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

This endpoint was summarized using the FAS. FAS included all randomized subjects.

Arm/Group Title	Faster Aspart	NovoRapid
Arm/Group Description	At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.	At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
Measure Participants	345	344
Baseline (week 0)	89.0 (16.9)	88.3 (16.7)
Week 26	91.6 (18.2)	90.8 (17.7)

Adverse Events

Time Frame	All treatment-emergent adverse events (AEs) were collected from the date on or after the first day of exposure to randomized treatment until no later than 7 days after the last day of randomised treatment
Adverse Event Reporting Description	Safety analysis set was used for the assessment of safety including AEs. The safety analysis set included all subjects who received at least one dose of test product (faster aspart) or comparator(NovoRapid).
Arm/Group Title	Faster Aspart		NovoRapid
Arm/Group Description	At randomization, all subjects started on 4 units of mealtime faster aspart (bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regiment. Faster aspart was administered (sc) 0-2 minutes before each main meal and dose was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.		At randomization, all subjects started on 4 units of mealtime NovoRapid®/NovoLog® (insulin aspart; bolus insulin) in combination with once-daily sc injection of insulin glargine (basal insulin) and metformin (oral) in a basal-bolus regimen. NovoRapid®/ NovoLog® was administered (sc) 0-2 minutes before each main meal, was titrated to the pre-prandial glycaemic target of 4.0-6.0 mmol/L (71-108 mg/dL) in a treat-to-target fashion according to the titration guideline. Dose adjustments were considered daily based on the pre-prandial and bedtime SMPG on the previous day. The dose adjustments were -1 or +1 if the pre-prandial or bedtime plasma glucose was <4.0 mmol/L or >6.0 mmol/L respectively. Basal insulin dose adjustments were allowed when needed. Metformin treatment continued without changing the frequency or dose.
All Cause Mortality
	Faster Aspart		NovoRapid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Faster Aspart		NovoRapid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/341 (4.4%)		24/341 (7%)
Cardiac disorders
Acute myocardial infarction	1/341 (0.3%)	1	1/341 (0.3%)	1
Angina unstable	0/341 (0%)	0	1/341 (0.3%)	1
Cardiomyopathy	1/341 (0.3%)	1	0/341 (0%)	0
Coronary artery occlusion	0/341 (0%)	0	1/341 (0.3%)	1
Myocardial ischaemia	1/341 (0.3%)	1	0/341 (0%)	0
Ear and labyrinth disorders
Aural polyp	1/341 (0.3%)	1	0/341 (0%)	0
Gastrointestinal disorders
Colitis ischaemic	0/341 (0%)	0	1/341 (0.3%)	1
Gastric polyps	0/341 (0%)	0	1/341 (0.3%)	1
Inguinal hernia	0/341 (0%)	0	1/341 (0.3%)	1
Infections and infestations
Bacteraemia	1/341 (0.3%)	1	0/341 (0%)	0
Cellulitis	0/341 (0%)	0	1/341 (0.3%)	1
Cholecystitis infective	1/341 (0.3%)	1	0/341 (0%)	0
Lobar pneumonia	1/341 (0.3%)	1	0/341 (0%)	0
Osteomyelitis	0/341 (0%)	0	1/341 (0.3%)	1
Otitis externa	1/341 (0.3%)	1	0/341 (0%)	0
Pneumonia	1/341 (0.3%)	1	0/341 (0%)	0
Injury, poisoning and procedural complications
Fall	0/341 (0%)	0	2/341 (0.6%)	2
Wrong drug administered	0/341 (0%)	0	1/341 (0.3%)	1
Investigations
Arteriogram coronary	0/341 (0%)	0	1/341 (0.3%)	1
Metabolism and nutrition disorders
Hypoglycaemia	2/341 (0.6%)	4	3/341 (0.9%)	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cardiac myxoma	1/341 (0.3%)	1	0/341 (0%)	0
Refractory anaemia with an excess of blasts	0/341 (0%)	0	1/341 (0.3%)	1
Renal cancer stage II	0/341 (0%)	0	1/341 (0.3%)	1
Transitional cell carcinoma	2/341 (0.6%)	2	0/341 (0%)	0
Nervous system disorders
Carotid artery occlusion	0/341 (0%)	0	1/341 (0.3%)	1
Carotid artery stenosis	0/341 (0%)	0	2/341 (0.6%)	2
Ischaemic stroke	0/341 (0%)	0	1/341 (0.3%)	1
Transient ischaemic attack	0/341 (0%)	0	2/341 (0.6%)	2
VIIth nerve paralysis	1/341 (0.3%)	1	0/341 (0%)	0
Renal and urinary disorders
Renal failure acute	0/341 (0%)	0	1/341 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/341 (0%)	0	1/341 (0.3%)	1
Pulmonary embolism	1/341 (0.3%)	1	1/341 (0.3%)	1
Skin and subcutaneous tissue disorders
Diabetic foot	0/341 (0%)	0	1/341 (0.3%)	1
Stasis dermatitis	0/341 (0%)	0	1/341 (0.3%)	1
Surgical and medical procedures
Cholecystectomy	1/341 (0.3%)	1	0/341 (0%)	0
Coronary artery bypass	0/341 (0%)	0	1/341 (0.3%)	1
Vascular disorders
Hypertension	1/341 (0.3%)	1	0/341 (0%)	0
Other (Not Including Serious) Adverse Events
	Faster Aspart		NovoRapid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/341 (14.4%)		53/341 (15.5%)
Infections and infestations
Nasopharyngitis	17/341 (5%)	20	24/341 (7%)	27
Upper respiratory tract infection	16/341 (4.7%)	19	22/341 (6.5%)	27
Urinary tract infection	20/341 (5.9%)	27	13/341 (3.8%)	16

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

At the end of the trial, one or more public disclosures may be prepared collaboratively by the Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.