Full STEP™: Efficacy and Safety of Basal-bolus Therapy, Comparing Stepwise Addition of Insulin Aspart Versus Complete Basal-bolus Regimen

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01165684
• Collaborator: (none)
• Enrollment: 401
• Locations: 67
• Arms: 2
• Duration (Months): 18
• Patients Per Site: 6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This trial is conducted in Europe, and North and South America. The aim of this clinical trial is to investigate if the two treatments are equally effective.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: insulin aspart; Drug: insulin aspart; Drug: insulin detemir	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 401 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomised, Controlled, Open Label, Multicentre, Multinational, Treat-to-target Trial Investigating the Efficacy and Safety of Intensification With Addition of Bolus Insulin Aspart in Subjects With Type 2 Diabetes Inadequately Controlled on Basal Insulin With or Without Oral Anti-diabetic Drugs: Step-wise Addition Versus Complete Basal-bolus Therapy
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Step-wise	Drug: insulin aspart; Insulin aspart added stepwise according to the largest meal following an evaluation of HbA1c. Doses individually adjusted.; Drug: insulin detemir; Insulin detemir as basal insulin, adminstered once daily. Doses individually adjusted.
Active Comparator: Basal-bolus	Drug: insulin aspart; Insulin aspart added before each main meal. Doses individually adjusted.; Drug: insulin detemir; Insulin detemir as basal insulin, adminstered once daily. Doses individually adjusted.

Outcome Measures

Primary Outcome Measures

1. Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 32 [Week 0, Week 32]

   Estimated mean change from baseline in HbA1c after 32 Weeks of treatment

Secondary Outcome Measures

1. Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 10 [Week 0, Week 10]

   Estimated mean change from baseline in HbA1c after 10 Weeks of treatment

2. Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 21 [Week 0, Week 21]

   Estimated mean change from baseline in HbA1c after 21 Weeks of treatment

3. Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 10 [Week 10]

   Proportion of subjects reaching HbA1c below 7.0% at Week 10

4. Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 21 [Week 21]

   Proportion of subjects reaching HbA1c below 7.0% at Week 21

5. Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 32 [Week 32]

   Proportion of subjects reaching HbA1c below 7.0% at Week 32

6. Fasting Plasma Glucose (FPG) at Week 10 [Week 10]

   Mean FPG at Week 10

7. Fasting Plasma Glucose (FPG) at Week 21 [Week 21]

   Mean FPG at Week 21

8. Fasting Plasma Glucose (FPG) at Week 32 [Week 32]

   Estimated Mean FPG at Week 32

9. Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 10 [Week 10]

   Mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 10

10. Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 21 [Week 21]

    Mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 21

11. Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 32 [Week 32]

    Estimated mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 32

12. Body Weight at Week 32 [Week 32]

    Estimated mean body weight after 32 Weeks of treatment

13. Body Mass Index (BMI) at Week 32 [Week 32]

    Estimated mean BMI after 32 Weeks of treatment

14. Hypoglycaemic Episodes (Rate of All Treatment Emergent Hypoglycaemia Episodes) [Week 0 to Week 32]

    A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment.

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 12 months

• Basal insulin treatment (NPH once or twice daily, insulin glargine once daily or insulin detemir once daily) for at least 6 months

• HbA1c: 7.0-9.0 % (both inclusive) by central laboratory analysis (one retest analysed at the central laboratory within a week is permitted with the result of the last sample being conclusive)

• BMI (Body Mass Index) less than 40.0 kg/m^2

Exclusion Criteria:

• Previous use of pre-mix or bolus insulin (allowed is previous use of bolus insulin only in case of a hospitalisation or a severe condition requiring intermittent use of bolus insulin for less than 14 consecutive days, but not during the last 6 months prior to screening visit (Visit 1)

• Use of GLP-1 (Glucagon-like peptide-1) receptor agonists or pramlintide within the last 6 months prior to prior to screening visit (Visit 1)

• Anticipated change in concomitant medication known to interfere significantly with glucose metabolism (e.g. systemic corticosteroids, beta-blockers, MAO (Monoamine oxidase) inhibitors, etc.)

• Cardiovascular disease, within the last 12 months prior to screening visit (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

• Uncontrolled treated/untreated severe hypertension (systolic blood pressure sitting at least 180 millimetre (mm) mercury (Hg) and/or diastolic blood pressure at least 100 mmHg). For Argentina: systolic blood pressure sitting at least 150 mmHg and/or diastolic blood pressure at least 90 mmHg

• Impaired liver function, defined as ALAT (Alanine aminotransferase) at least 2.5 times upper limit of normal (one retest analysed at the central laboratory within a week is permitted with the result of the last sample being conclusive)

• Impaired renal function defined as serum creatinine above 135 micromol/L (above 1.5 mg/dL) for males and above 110 micromol/L (above 1.2 mg/dL) for females; and, if required by the locally applicable metformin label, glomerular filtration rate below 60 ml/min, calculated by the Cockroft & Gault formula). One retest within a week is permitted with the result of the last sample being conclusive

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

• Proliferative retinopathy or maculopathy requiring treatment according to the Investigator

• Treatment with OADs (Oral anti-diabetic drug) contraindicated or unapproved for combination treatment with insulin (according to local OAD label)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Birmingham	Alabama	United States	35216
2	Novo Nordisk Investigational Site	Mesa	Arizona	United States	85206
3	Novo Nordisk Investigational Site	Scottsdale	Arizona	United States	85251
4	Novo Nordisk Investigational Site	Fresno	California	United States	93720
5	Novo Nordisk Investigational Site	Hialeah	Florida	United States	33012
6	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32204
7	Novo Nordisk Investigational Site	Kissimmee	Florida	United States	34741
8	Novo Nordisk Investigational Site	Miami	Florida	United States	33136
9	Novo Nordisk Investigational Site	Miami	Florida	United States	33165
10	Novo Nordisk Investigational Site	Plantation	Florida	United States	33313
11	Novo Nordisk Investigational Site	Port Charlotte	Florida	United States	33952
12	Novo Nordisk Investigational Site	Atlanta	Georgia	United States	30308-2253
13	Novo Nordisk Investigational Site	Roswell	Georgia	United States	30076
14	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60616
15	Novo Nordisk Investigational Site	Indianapolis	Indiana	United States	46254
16	Novo Nordisk Investigational Site	Metairie	Louisiana	United States	70002
17	Novo Nordisk Investigational Site	Rockville	Maryland	United States	20852
18	Novo Nordisk Investigational Site	Springfield	Massachusetts	United States	01199
19	Novo Nordisk Investigational Site	Brooklyn Center	Minnesota	United States	55430
20	Novo Nordisk Investigational Site	Jefferson City	Missouri	United States	65109
21	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89148
22	Novo Nordisk Investigational Site	Lawrenceville	New Jersey	United States	08648
23	Novo Nordisk Investigational Site	New Windsor	New York	United States	12553
24	Novo Nordisk Investigational Site	Beavercreek	Ohio	United States	45432
25	Novo Nordisk Investigational Site	Dayton	Ohio	United States	45439
26	Novo Nordisk Investigational Site	Kettering	Ohio	United States	45429
27	Novo Nordisk Investigational Site	Altoona	Pennsylvania	United States	16602
28	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19107
29	Novo Nordisk Investigational Site	Greer	South Carolina	United States	29651
30	Novo Nordisk Investigational Site	Dallas	Texas	United States	75235-6233
31	Novo Nordisk Investigational Site	Salt Lake City	Utah	United States	84102
32	Novo Nordisk Investigational Site	Salt Lake City	Utah	United States	84107
33	Novo Nordisk Investigational Site	Newport News	Virginia	United States	23606
34	Novo Nordisk Investigational Site	Buenos Aires		Argentina	B1636DSU
35	Novo Nordisk Investigational Site	Buenos Aires		Argentina	B1704ETD
36	Novo Nordisk Investigational Site	Buenos Aires		Argentina	C1250AAN
37	Novo Nordisk Investigational Site	Buenos Aires		Argentina	C1425AGC
38	Novo Nordisk Investigational Site	Caba		Argentina	C1440AAD
39	Novo Nordisk Investigational Site	Córdoba		Argentina	X5006IKK
40	Novo Nordisk Investigational Site	Mendoza		Argentina	5500
41	Novo Nordisk Investigational Site	Goiania	Goias	Brazil	74043-011
42	Novo Nordisk Investigational Site	São Paulo	Sao Paulo	Brazil	01244-030
43	Novo Nordisk Investigational Site	Campinas		Brazil	13084-971
44	Novo Nordisk Investigational Site	Porto Alegre		Brazil	90035-170
45	Novo Nordisk Investigational Site	Rio de Janeiro		Brazil	20211-340
46	Novo Nordisk Investigational Site	Calgary	Alberta	Canada	T2N 4L7
47	Novo Nordisk Investigational Site	Coquitlam	British Columbia	Canada	V3K 3P4
48	Novo Nordisk Investigational Site	Langley	British Columbia	Canada	V3A 4H9
49	Novo Nordisk Investigational Site	Vancouver	British Columbia	Canada	V5Z 1M9
50	Novo Nordisk Investigational Site	Victoria	British Columbia	Canada	V8V 3N7
51	Novo Nordisk Investigational Site	Chatham	Ontario	Canada	N7L 1C1
52	Novo Nordisk Investigational Site	Kingston	Ontario	Canada	K7L 2V7
53	Novo Nordisk Investigational Site	Gatineau	Quebec	Canada	J8V 2P5
54	Novo Nordisk Investigational Site	Lachine	Quebec	Canada	H8S 2E4
55	Novo Nordisk Investigational Site	Mirabel	Quebec	Canada	J7J 2K8
56	Novo Nordisk Investigational Site	Montreal	Quebec	Canada	H2W 1R7
57	Novo Nordisk Investigational Site	Montreal	Quebec	Canada	H3T 1E2
58	Novo Nordisk Investigational Site	Marseille		France	13009
59	Novo Nordisk Investigational Site	Narbonne		France	11108
60	Novo Nordisk Investigational Site	Saint Herblain		France	44800
61	Novo Nordisk Investigational Site	Sète		France	34200
62	Novo Nordisk Investigational Site	Venissieux		France	69200
63	Novo Nordisk Investigational Site	Skopje		Macedonia, The Former Yugoslav Republic of	1000
64	Novo Nordisk Investigational Site	Brezice		Slovenia	8250
65	Novo Nordisk Investigational Site	Kranj		Slovenia	4000
66	Novo Nordisk Investigational Site	Novo mesto		Slovenia	8000
67	Novo Nordisk Investigational Site	Trbovlje		Slovenia	1420

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: NCT01165684
• Other Study ID Numbers: ANA-3786; 2010-018974-19; U1111-1116-0908
• First Posted: Jul 20, 2010
• Last Update Posted: Feb 17, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination; Insulin Detemir

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 69 sites in 7 countries: Argentina (7), Brazil (5), Canada (12), France (7), Macedonia (1), Slovenia (4), and the US (31). Of 12 sites in Canada, one site (Site 303) closed early on 07-Mar-2011.
Pre-assignment Detail	Subjects on pre-trial metformin and pioglitazone continued their medication.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Period Title: Overall Study
STARTED	201	200
Exposed	198	199
COMPLETED	173	148
NOT COMPLETED	28	52

Baseline Characteristics

Arm/Group Title	Step-wise	Basal-bolus	Total
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.	Total of all reporting groups
Overall Participants	201	200	401
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.0 (9.1)	59.6 (9.5)	59.8 (9.3)
Gender (Count of Participants)
Female	97 48.3%	101 50.5%	198 49.4%
Male	104 51.7%	99 49.5%	203 50.6%
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	88.9 (18.7)	86.1 (15.2)	87.5 (17.1)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31.5 (4.8)	30.7 (4.6)	31.1 (4.7)
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	7.9 (0.6)	7.9 (0.6)	7.9 (0.6)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	7.0 (1.9)	6.9 (1.6)	6.9 (1.8)

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 32
Description	Estimated mean change from baseline in HbA1c after 32 Weeks of treatment
Time Frame	Week 0, Week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 32.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	195	188
Mean (Standard Error) [percentage of glycosylated haemoglobin]	-0.98 (0.06)	-1.12 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was considered confirmed if the upper bound of the two-sided 95% CI was below or equal to 0.4% or equivalently if the p-value for the one-sided test of was less than or equal to 2.5%, where D is the mean treatment difference (step-wise regimen minus basal-bolus regimen).
Statistical Test of Hypothesis	p-Value	0.088
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	0.14
	Confidence Interval	() 95%; -0.02 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 10
Description	Estimated mean change from baseline in HbA1c after 10 Weeks of treatment
Time Frame	Week 0, Week 10

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 376 subjects contributed to the statistical analysis at Week 10.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	193	183
Mean (Standard Error) [percentage of glycosylated haemoglobin]	-0.45 (0.05)	-1.00 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	0.55
	Confidence Interval	() 95%; 0.42 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 21
Description	Estimated mean change from baseline in HbA1c after 21 Weeks of treatment
Time Frame	Week 0, Week 21

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 21.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	195	188
Mean (Standard Error) [percentage of glycosylated haemoglobin]	-0.78 (0.06)	-1.15 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, Mean
	Estimated Value	0.37
	Confidence Interval	() 95%; 0.21 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 10
Description	Proportion of subjects reaching HbA1c below 7.0% at Week 10
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 376 subjects contributed to the statistical analysis at Week 10.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	193	183
Number [percentage (%) of subjects]	19.2	56.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	6.85
	Confidence Interval	() 95%; 4.12 to 11.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 21
Description	Proportion of subjects reaching HbA1c below 7.0% at Week 21
Time Frame	Week 21

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 21.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	195	188
Number [percentage (%) of subjects]	45.1	65.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.38
	Confidence Interval	() 95%; 1.56 to 3.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 32
Description	Proportion of subjects reaching HbA1c below 7.0% at Week 32
Time Frame	Week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 32.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	195	188
Number [percentage (%) of subjects]	55.9	63.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.146
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.36
	Confidence Interval	() 95%; 0.90 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Fasting Plasma Glucose (FPG) at Week 10
Description	Mean FPG at Week 10
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 368 subjects contributed to data at Week 10.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	186	182
Mean (Standard Deviation) [mmol/L]	7.1 (1.9)	6.7 (1.9)

8. Secondary Outcome

Title	Fasting Plasma Glucose (FPG) at Week 21
Description	Mean FPG at Week 21
Time Frame	Week 21

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the data at Week 21.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	195	188
Mean (Standard Deviation) [mmol/L]	7.1 (2.3)	7.0 (2.3)

9. Secondary Outcome

Title	Fasting Plasma Glucose (FPG) at Week 32
Description	Estimated Mean FPG at Week 32
Time Frame	Week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 32.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	195	188
Mean (Standard Error) [mmol/L]	7.12 (0.17)	7.01 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.635
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Estimated Mean
	Estimated Value	0.12
	Confidence Interval	() 95%; -0.37 to 0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 10
Description	Mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 10
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 326 subjects contributed to the data at Week 10.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	165	161
Mean (Standard Deviation) [mmol/L]	2.3 (2.2)	1.4 (2.0)

11. Secondary Outcome

Title	Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 21
Description	Mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 21
Time Frame	Week 21

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 343 subjects contributed to the data at Week 21.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	176	167
Mean (Standard Deviation) [mmol/L]	1.9 (1.8)	1.5 (1.8)

12. Secondary Outcome

Title	Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 32
Description	Estimated mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 32
Time Frame	Week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 352 subjects contributed to the statistical analysis at Week 32.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	182	170
Mean (Standard Deviation) [mmol/L]	1.64 (0.12)	1.28 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Estimated mean
	Estimated Value	0.36
	Confidence Interval	() 95%; 0.01 to 0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Body Weight at Week 32
Description	Estimated mean body weight after 32 Weeks of treatment
Time Frame	Week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 378 subjects contributed to the statistical analysis at Week 32.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	190	188
Mean (Standard Error) [kg]	89.32 (0.28)	89.80 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.228
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Estimated mean
	Estimated Value	-0.48
	Confidence Interval	() 95%; -1.25 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Body Mass Index (BMI) at Week 32
Description	Estimated mean BMI after 32 Weeks of treatment
Time Frame	Week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 378 subjects contributed to the statistical analysis at Week 32.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	190	188
Mean (Standard Error) [kg/m^2]	31.86 (0.10)	32.03 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Step-wise, Basal-bolus
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.224
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Estimated mean
	Estimated Value	-0.17
	Confidence Interval	() 95%; -0.45 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Hypoglycaemic Episodes (Rate of All Treatment Emergent Hypoglycaemia Episodes)
Description	A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment.
Time Frame	Week 0 to Week 32

Outcome Measure Data

Analysis Population Description

Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator. 397 subjects contributed with data.

Arm/Group Title	Step-wise	Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.	In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
Measure Participants	198	199
Number [Episodes /year of patient exposure]	33.47	57.56

Adverse Events

Time Frame	Adverse events were captured from the time of consent until 32 weeks of treatment and if needed were followed up after the final visit
Adverse Event Reporting Description	Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator
Arm/Group Title	Step-wise		Basal-bolus
Arm/Group Description	In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication.		In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication.
All Cause Mortality
	Step-wise		Basal-bolus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Step-wise		Basal-bolus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/198 (9.1%)		15/199 (7.5%)
Cardiac disorders
Acute myocardial infarction	0/198 (0%)	0	1/199 (0.5%)	1
Atrial fibrillation	1/198 (0.5%)	1	0/199 (0%)	0
Coronary artery disease	1/198 (0.5%)	1	0/199 (0%)	0
Myocardial ischaemia	1/198 (0.5%)	1	0/199 (0%)	0
Supraventricular tachycardia	1/198 (0.5%)	1	0/199 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	1/198 (0.5%)	1	0/199 (0%)	0
Gastrointestinal fistula	0/198 (0%)	0	1/199 (0.5%)	1
Intestinal obstruction	1/198 (0.5%)	1	0/199 (0%)	0
Pancreatitis	1/198 (0.5%)	1	0/199 (0%)	0
Hepatobiliary disorders
Cholelithiasis	1/198 (0.5%)	1	0/199 (0%)	0
Infections and infestations
Bacterial translocation	0/198 (0%)	0	1/199 (0.5%)	1
Erysipelas	0/198 (0%)	0	1/199 (0.5%)	1
Gastroenteritis	1/198 (0.5%)	1	0/199 (0%)	0
Injection site infection	1/198 (0.5%)	1	0/199 (0%)	0
Pneumonia	1/198 (0.5%)	1	0/199 (0%)	0
Pyelonephritis acute	1/198 (0.5%)	1	0/199 (0%)	0
Injury, poisoning and procedural complications
Intentional overdose	1/198 (0.5%)	1	0/199 (0%)	0
Wrong drug administered	0/198 (0%)	0	1/199 (0.5%)	1
Metabolism and nutrition disorders
Hypoglycaemia	2/198 (1%)	3	5/199 (2.5%)	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gallbladder cancer	1/198 (0.5%)	1	0/199 (0%)	0
Metastases to liver	1/198 (0.5%)	1	0/199 (0%)	0
Metastatic gastric cancer	1/198 (0.5%)	1	0/199 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/198 (0.5%)	1	0/199 (0%)	0
Hypoglycaemic seizure	0/198 (0%)	0	1/199 (0.5%)	1
Hypoglycaemic unconsciousness	0/198 (0%)	0	3/199 (1.5%)	3
Psychiatric disorders
Acute stress disorder	1/198 (0.5%)	1	0/199 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/198 (0%)	0	1/199 (0.5%)	1
Lower respiratory tract inflammation	0/198 (0%)	0	1/199 (0.5%)	1
Vascular disorders
Orthostatic hypotension	1/198 (0.5%)	1	0/199 (0%)	0
Peripheral arterial occlusive disease	1/198 (0.5%)	1	0/199 (0%)	0
Peripheral vascular disorder	0/198 (0%)	0	1/199 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Step-wise		Basal-bolus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/198 (20.2%)		47/199 (23.6%)
Gastrointestinal disorders
Diarrhoea	8/198 (4%)	10	10/199 (5%)	10
General disorders
Oedema peripheral	4/198 (2%)	5	10/199 (5%)	10
Infections and infestations
Influenza	10/198 (5.1%)	11	13/199 (6.5%)	14
Nasopharyngitis	16/198 (8.1%)	19	13/199 (6.5%)	18
Nervous system disorders
Headache	10/198 (5.1%)	15	11/199 (5.5%)	13

Limitations/Caveats

A higher proportion of subjects did not complete the trial in the basal-bolus arm (52 subjects, 26.0%) than in the step-wise arm (28 subjects, 13.9%).

More Information

Certain Agreements

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

Novo Nordisk maintains the right to be informed of any Investigator plans for publication and to review any scientific paper, presentation, communication or other information concerning the investigation described in this protocol. Novo Nordisk reserves the right to prior review of such publications and to ask for delay of publication of individual site results until after the primary manuscript is accepted for publication.