onset® 3: Efficacy and Safety of FIAsp in a Basal-bolus Regimen Versus Basal Insulin Therapy, Both in Combination With Metformin in Adult Subjects With Type 2 Diabetes

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01850615
• Collaborator: (none)
• Enrollment: 323
• Locations: 58
• Arms: 2
• Actual Duration (Months): 13.8
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This trial is conducted in Asia, Europe, South America, and the United States of America (USA).

The aim of the trial is to investigate efficacy and safety of FIAsp in a basal-bolus regimen versus basal insulin therapy, both in combination with metformin in adult subjects with type 2 diabetes.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 323 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of FIAsp in a Basal-bolus Regimen Versus Basal Insulin Therapy, Both in Combination With Metformin in Adult Subjects With Type 2 Diabetes
• Actual Study Start Date: Sep 23, 2013
• Actual Primary Completion Date: Nov 17, 2014
• Actual Study Completion Date: Nov 17, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FIAsp and basal insulin + metformin Subjects will receive FIAsp combined with their pre-trial basal insulin (insulin human, insulin detemir or insulin glargine) treatment in combination with their pre-trial metformin.	Drug: Faster-acting insulin aspart; Administrated subcutaneously (s.c., under the skin) at each main meal.; Other Names: NN1218 ; Drug: basal insulin; Administrated subcutaneously (s.c., under the skin) once daily.
Active Comparator: Basal insulin + metformin Subjects will continue their pre-trial basal insulin (insulin human, insulin detemir or insulin glargine) treatment in combination with their pre-trial metformin.	Drug: basal insulin; Administrated subcutaneously (s.c., under the skin) once daily.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in HbA1c [Week 0, week 18]

   For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the "end of trial" data containing last available measurements.

Secondary Outcome Measures

1. Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) [After 18 weeks of randomised treatment]

   For this endpoint the "end of trial" data containing last available measurements are presented. PPG measurements were recorded by the subjects at 2 hours after each meal (breakfast, lunch and main evening meal) as part of three 7-point profiles (SMPG) prior to the visits. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.

2. Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal) [After 18 weeks of randomised treatment]

   For this endpoint the "end of trial" data containing last available measurements are presented. Prandial PG increment for each meal (breakfast, lunch, main evening meal) was derived from the 7-point profiles (SMPG) as the difference between the PPG value 2 hours after each meal and the PG value before each meal. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.

3. Change From Baseline in Body Weight [Week 0, week 18]

   For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the "end of trial" data containing last available measurements.

4. Number of Treatment Emergent Hypoglycaemic Episodes [Weeks 0-18]

   Plasma glucose (PG) was measured and recorded when a hypoglycaemic episode was suspected. All PG values ≤3.9 mmol/L (70 mg/dL) or >3.9 mmol/L (70 mg/dL) when they occurred in conjunction with hypoglycaemic symptoms were recorded by the subject. Numbers of treatment emergent hypoglycaemic episodes were recorded during 18 weeks of treatment.

5. Number of Adverse Events [Weeks 0-18]

   All adverse events (AEs) described here refer to treatment emergent adverse events (TEAE). A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment, week 18.

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 at least 6 months prior to the screening visit (Visit 1)

• Current treatment with once daily insulin detemir, insulin glargine or human isophane insulin, NPH 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 Dipeptidyl peptidase-IV 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) 7.5-9.5% (58 - 80 mmol/mol) (both inclusive) in the metformin group at the screening visit (Visit 1) or b) 7.5-9.0% (58 - 75 mmol/mol) (both inclusive) in the metformin + other oral antidiabetic drug (OAD) (sulphonylurea (SU), glinide, dipeptidyl peptidase-IV (DDP-IV) inhibitors, alpha-glucosidase inhibitors (AGI) combination group at the screening visit (Visit 1)

• Body mass index (BMI) equal or less than 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 of consecutive treatment) and not within 3 months prior to the screening visit (Visit 1)

• Use of Glucagon-like peptide-1 (GLP-1) agonists and/or Thiazolidinediones (TZD) within the last 3 months prior to screening (visit 1)

• Recurrent severe hypoglycaemia (more than one 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Birmingham	Alabama	United States	35211
2	Novo Nordisk Investigational Site	Birmingham	Alabama	United States	35216
3	Novo Nordisk Investigational Site	Peoria	Arizona	United States	85381
4	Novo Nordisk Investigational Site	Little Rock	Arkansas	United States	72205
5	Novo Nordisk Investigational Site	Santa Ana	California	United States	92705
6	Novo Nordisk Investigational Site	Tarzana	California	United States	91356-3551
7	Novo Nordisk Investigational Site	Colorado Springs	Colorado	United States	80907
8	Novo Nordisk Investigational Site	Colorado Springs	Colorado	United States	80922
9	Novo Nordisk Investigational Site	Clearwater	Florida	United States	33765
10	Novo Nordisk Investigational Site	Pembroke Pines	Florida	United States	33028
11	Novo Nordisk Investigational Site	Conyers	Georgia	United States	30094-5965
12	Novo Nordisk Investigational Site	New Orleans	Louisiana	United States	70121
13	Novo Nordisk Investigational Site	Rockville	Maryland	United States	20852
14	Novo Nordisk Investigational Site	Boston	Massachusetts	United States	02118
15	Novo Nordisk Investigational Site	Kalamazoo	Michigan	United States	49009
16	Novo Nordisk Investigational Site	Omaha	Nebraska	United States	68144
17	Novo Nordisk Investigational Site	Henderson	Nevada	United States	89052
18	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89120
19	Novo Nordisk Investigational Site	Brooklyn	New York	United States	11229
20	Novo Nordisk Investigational Site	Asheboro	North Carolina	United States	27203
21	Novo Nordisk Investigational Site	Cincinnati	Ohio	United States	45242
22	Novo Nordisk Investigational Site	Oklahoma City	Oklahoma	United States	73104
23	Novo Nordisk Investigational Site	Downingtown	Pennsylvania	United States	19335-2620
24	Novo Nordisk Investigational Site	Reading	Pennsylvania	United States	19609
25	Novo Nordisk Investigational Site	Greenville	South Carolina	United States	29605-4254
26	Novo Nordisk Investigational Site	Greer	South Carolina	United States	29651
27	Novo Nordisk Investigational Site	Memphis	Tennessee	United States	38119-3821
28	Novo Nordisk Investigational Site	Fort Worth	Texas	United States	76132
29	Novo Nordisk Investigational Site	Houston	Texas	United States	77025-1669
30	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78229
31	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77478
32	Novo Nordisk Investigational Site	Ogden	Utah	United States	84405
33	Novo Nordisk Investigational Site	Buenos Aires		Argentina	C1250AAN
34	Novo Nordisk Investigational Site	Capital Federal		Argentina	C1056ABJ
35	Novo Nordisk Investigational Site	Córdoba		Argentina	X5006IKK
36	Novo Nordisk Investigational Site	Godoy Cruz		Argentina	M5501ARP
37	Novo Nordisk Investigational Site	San Isidro		Argentina	B1642DCD
38	Novo Nordisk Investigational Site	Hyderabad	Andhra Pradesh	India	500034
39	Novo Nordisk Investigational Site	Hyderabad	Andhra Pradesh	India	500082
40	Novo Nordisk Investigational Site	Visakhapatnam	Andhra Pradesh	India	530002
41	Novo Nordisk Investigational Site	Bangalore	Karnataka	India	560 017
42	Novo Nordisk Investigational Site	Mumbai	Maharashtra	India	400007
43	Novo Nordisk Investigational Site	Mumbai	Maharashtra	India	400058
44	Novo Nordisk Investigational Site	New Dehli	New Delhi	India	110029
45	Novo Nordisk Investigational Site	Chandigarh	Punjab	India	160012
46	Novo Nordisk Investigational Site	Coimbatore	Tamil Nadu	India	641018
47	Novo Nordisk Investigational Site	Guadalajara	Jalisco	Mexico	44150
48	Novo Nordisk Investigational Site	Guadalajara	Jalisco	Mexico	44650
49	Novo Nordisk Investigational Site	Mexico City	México, D.F.	Mexico	03300
50	Novo Nordisk Investigational Site	Targu Mures	Mures	Romania	540142
51	Novo Nordisk Investigational Site	Ploiesti	Prahova	Romania	100097
52	Novo Nordisk Investigational Site	Timisoara	Timis	Romania	300125
53	Novo Nordisk Investigational Site	Brasov		Romania	500269
54	Novo Nordisk Investigational Site	Suceava		Romania	720237
55	Novo Nordisk Investigational Site	Brezice		Slovenia	8250
56	Novo Nordisk Investigational Site	Koper		Slovenia	SI-6000
57	Novo Nordisk Investigational Site	Kranj		Slovenia	4000
58	Novo Nordisk Investigational Site	Novo mesto		Slovenia	8000

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

• Peters AL, Piletič M, Ejstrud J, Salvesen-Sykes K, Snyder J, Bowering K. Baseline nocturnal glucose change: A predictor of the treatment effect of bolus intensification in insulin-treated type 2 diabetes. Diabetes Obes Metab. 2019 Jul;21(7):1752-1756. doi: 10.1111/dom.13729. Epub 2019 Apr 23.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01850615
• Other Study ID Numbers: NN1218-4049; 2012-005583-10; U1111-1137-6242; CTRI/2014/01/004289
• First Posted: May 9, 2013
• Last Update Posted: Jun 12, 2019
• Last Verified: May 1, 2019

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 51 sites in 6 countries as follows: Argentina: 4 sites; India: 8 sites; Mexico: 3 sites; Romania: 5 sites; Slovenia: 4 sites; United States: 27 sites.
Pre-assignment Detail	A total of 555 subjects were screened, of which 232 subjects were screening failures and 323 subjects were enrolled and entered the run-in (pre-assignment) period. Of those, 87 subjects were run-in failures. Hence, 236 subjects were randomized to the 18 weeks of treatment period.

Arm/Group Title	Faster Aspart + Basal	Basal
Arm/Group Description	During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different plasma glucose (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given once daily (OD), in the evening, at approximately the same time each day.	During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Period Title: Overall Study
STARTED	116	120
Exposed	115	120
COMPLETED	107	115
NOT COMPLETED	9	5

Baseline Characteristics

Arm/Group Title	Faster Aspart + Basal	Basal	Total
Arm/Group Description	During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.	During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.	Total of all reporting groups
Overall Participants	116	120	236
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.5 (9.9)	57.4 (8.5)	57.4 (9.2)
Sex: Female, Male (Count of Participants)
Female	61 52.6%	61 50.8%	122 51.7%
Male	55 47.4%	59 49.2%	114 48.3%
Glycosylated haemoglobin (HbA1c) (Percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of glycosylated haemoglobin]	7.93 (0.69)	7.92 (0.68)	7.93 (0.69)
Body weight (Kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg]	82.2 (16.2)	85.1 (17.3)	83.7 (16.8)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in HbA1c
Description	For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the "end of trial" data containing last available measurements.
Time Frame	Week 0, week 18

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomised subjects.

Arm/Group Title	Faster Aspart + Basal	Basal
Arm/Group Description	During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.	During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Measure Participants	116	120
Baseline	7.93 (0.69)	7.92 (0.68)
Week 18	6.78 (0.92)	7.7 (0.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Faster Aspart + Basal, Basal
	Comments	Change from baseline in HbA1c after 18 weeks of treatment was analysed using a mixed-effect model for repeated measurements (MMRM) where all calculated changes in HbA1c from baseline at visits 16, 22 and 28 were included in the analysis. This model included treatment, region and strata as fixed factors, subject as random effect, baseline HbA1c as covariate and interaction between all fixed effects and visit, and between the covariate and visit.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.94
	Confidence Interval	(2-Sided) 95%; -1.17 to -0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Superiority was considered confirmed if the upper bound of the two-sided 95% confidence interval (CI) for the estimated treatment difference (faster aspart+basal minus basal only), which was calculated using the FAS, was below 0%.

2. Secondary Outcome

Title	Self-measured Plasma Glucose (SMPG) 7-point Profile: Post Prandial Plasma Glucose (PPG), Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal)
Description	For this endpoint the "end of trial" data containing last available measurements are presented. PPG measurements were recorded by the subjects at 2 hours after each meal (breakfast, lunch and main evening meal) as part of three 7-point profiles (SMPG) prior to the visits. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.
Time Frame	After 18 weeks of randomised treatment

Outcome Measure Data

Analysis Population Description

FAS included all randomised subjects. Number analysed for individual time-points = treatment wise number of subjects who contributed to analysis.

Arm/Group Title	Faster Aspart + Basal	Basal
Arm/Group Description	During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.	During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Measure Participants	116	120
PPG breakfast; SMPG	7.2 (1.8)	9 (2.4)
PPG lunch; SMPG	7.1 (1.9)	9.7 (2.6)
PPG main evening meal; SMPG	7.4 (1.9)	10.1 (2.9)

3. Secondary Outcome

Title	Self-measured Plasma Glucose (SMPG) 7-point Profile: Prandial Plasma Glucose (PG) Increment, Overall 2-hour Mean (of Breakfast, Lunch, Main Evening Meal)
Description	For this endpoint the "end of trial" data containing last available measurements are presented. Prandial PG increment for each meal (breakfast, lunch, main evening meal) was derived from the 7-point profiles (SMPG) as the difference between the PPG value 2 hours after each meal and the PG value before each meal. Individual mean meal PPG (post-breakfast, post-lunch, post-main evening meal) was derived from the three measurements.
Time Frame	After 18 weeks of randomised treatment

Outcome Measure Data

Analysis Population Description

FAS included all randomised subjects. Number analysed for individual time-points = treatment wise number of subjects who contributed to analysis.

Arm/Group Title	Faster Aspart + Basal	Basal
Arm/Group Description	During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.	During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Measure Participants	116	120
Breakfast increment; SMPG	1.2 (1.8)	2.9 (2.4)
Lunch increment; SMPG	0.9 (2.0)	1.8 (2.2)
Main evening meal increment; SMPG	0.7 (1.7)	1.4 (1.9)

4. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	For this endpoint, baseline (week 0) and week 18 data are presented, where week 18 data are the "end of trial" data containing last available measurements.
Time Frame	Week 0, week 18

Outcome Measure Data

Analysis Population Description

FAS included all randomised subjects.

Arm/Group Title	Faster Aspart + Basal	Basal
Arm/Group Description	During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.	During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Measure Participants	116	120
Baseline	82.2 (16.2)	85.1 (17.3)
Week 18	83.9 (16.9)	85.4 (17.5)

5. Secondary Outcome

Title	Number of Treatment Emergent Hypoglycaemic Episodes
Description	Plasma glucose (PG) was measured and recorded when a hypoglycaemic episode was suspected. All PG values ≤3.9 mmol/L (70 mg/dL) or >3.9 mmol/L (70 mg/dL) when they occurred in conjunction with hypoglycaemic symptoms were recorded by the subject. Numbers of treatment emergent hypoglycaemic episodes were recorded during 18 weeks of treatment.
Time Frame	Weeks 0-18

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or its comparator.

Arm/Group Title	Faster Aspart + Basal	Basal
Arm/Group Description	During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.	During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Measure Participants	115	120
Number [Number of episodes]	1908	347

6. Secondary Outcome

Title	Number of Adverse Events
Description	All adverse events (AEs) described here refer to treatment emergent adverse events (TEAE). A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment, week 18.
Time Frame	Weeks 0-18

Outcome Measure Data

Analysis Population Description

The SAS included all subjects receiving at least one dose of the investigational product or its comparator.

Arm/Group Title	Faster Aspart + Basal	Basal
Arm/Group Description	During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.	During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
Measure Participants	115	120
Number [Number of events]	123	121

Adverse Events

Time Frame	During 18 weeks of randomised treatment period + 7 days of follow-up period.
Adverse Event Reporting Description	All AEs described here refer to TEAEs. The SAS included all subjects receiving at least one dose of the investigational product or its comparator.
Arm/Group Title	Faster Aspart + Basal		Basal
Arm/Group Description	During the 18-week treatment period, subjects received subcutaneous (s.c., under the skin) injection of faster aspart (bolus insulin) along with s.c. basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different PG levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. Faster aspart was administered 0-2 minutes before each main meal (i.e., breakfast, lunch and main evening meal). The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.		During the 18-week treatment period, subjects received s.c. injection of basal insulin (insulin detemir or insulin glargine or NPH insulin) and metformin. Treatment recommendations were developed for the different trial products specifying the recommended dose adjustments at different (PG) levels. Trial products were titrated according to the insulin dosing recommendations provided during the study. No maximum dose of insulin was specified as doses were titrated individually. The basal insulin injection was to be given OD, in the evening, at approximately the same time each day.
All Cause Mortality
	Faster Aspart + Basal		Basal
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Faster Aspart + Basal		Basal
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/115 (5.2%)		5/120 (4.2%)
Cardiac disorders
Cardiovascular disorder	1/115 (0.9%)	1	0/120 (0%)	0
Hepatobiliary disorders
Cholelithiasis	0/115 (0%)	0	1/120 (0.8%)	1
Infections and infestations
Respiratory tract infection	1/115 (0.9%)	1	0/120 (0%)	0
Injury, poisoning and procedural complications
Carbon monoxide poisoning	0/115 (0%)	0	1/120 (0.8%)	1
Fall	2/115 (1.7%)	2	1/120 (0.8%)	1
Wrong drug administered	1/115 (0.9%)	1	0/120 (0%)	0
Metabolism and nutrition disorders
Hypoglycaemia	2/115 (1.7%)	2	0/120 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/115 (0%)	0	1/120 (0.8%)	1
Malignant respiratory tract neoplasm	0/115 (0%)	0	1/120 (0.8%)	1
Nervous system disorders
Hypoglycaemic unconsciousness	0/115 (0%)	0	1/120 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
Lung infiltration	0/115 (0%)	0	1/120 (0.8%)	1
Vascular disorders
Peripheral arterial occlusive disease	1/115 (0.9%)	1	0/120 (0%)	0
Other (Not Including Serious) Adverse Events
	Faster Aspart + Basal		Basal
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/115 (1.7%)		6/120 (5%)
Gastrointestinal disorders
Diarrhoea	2/115 (1.7%)	4	6/120 (5%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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