iDEAt2: A Trial Investigating the Efficacy and Safety of Insulin Detemir Versus Insulin NPH in Combination With Metformin and Diet/Exercise in Children and Adolescents With Type 2 Diabetes Insufficiently Controlled on Metformin With or Without Other Oral Antidiabetic Drug(s) With or Without Basal Insulin

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02131272
• Collaborator: (none)
• Enrollment: 42
• Locations: 82
• Arms: 2
• Actual Duration (Months): 24.1
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This trial is conducted globally. The aim of the trial is to investigate the efficacy and safety of insulin detemir versus insulin Neutral Protamine Hagedorn (NPH) in combination with the maximum tolerated dose of metformin and diet/exercise on glycaemic control in children and adolescents with type 2 diabetes insufficiently controlled on the maximum tolerated dose of metformin with or without other oral antidiabetic drug(s) with or without basal insulin.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: Insulin detemir; Drug: Insulin NPH; Behavioral: Diet/exercise	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 26-week Open Label, Randomised, 2-armed, Parallel Group, Multi-centre Trial Investigating Efficacy and Safety of Insulin Detemir Versus Insulin Neutral Protamine Hagedorn in Combination With the Maximum Tolerated Dose of Metformin and Diet/Exercise on Glycaemic Control in Children and Adolescents With Type 2 Diabetes Insufficiently Controlled on the Maximum Tolerated Dose of Metformin ± Other Oral Antidiabetic Drug(s) ± Basal Insulin
• Actual Study Start Date: Jun 11, 2014
• Actual Primary Completion Date: Jun 14, 2016
• Actual Study Completion Date: Jun 14, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Insulin detemir and diet/exercise Current OADs i.e. metformin or other OADs are continued unchanged	Drug: Insulin NPH; Administered subcutaneously (s.c., under the skin) once or twice daily. The subjects' pre-trial OADs i.e. metformin treatment should continue unchanged during the treatment period.; Behavioral: Diet/exercise; Intervention will be performed through family based changes in eating and activity behaviours.
Active Comparator: Insulin NPH and diet/exercise Current OADs i.e. metformin or other OADs are continued unchanged	Drug: Insulin detemir; Administered subcutaneously (s.c., under the skin) once or twice daily. The subjects' pre-trial OAD's i.e. metformin treatment should continue unchanged during the treatment period.; Behavioral: Diet/exercise; Intervention will be performed through family based changes in eating and activity behaviours.

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c (Glycosylated Haemoglobin) [week 0, week 26]

   Estimated mean change in HbA1c (glycosylated haemoglobin) from baseline to week 26.

Secondary Outcome Measures

1. Change in Body Weight Standard Deviation Score (SDS) [week 0, week 26]

   Change in body weight standard deviation score (SDS) from baseline to week 26. In order to reduce the variability in body weight measurements, SDS were calculated. SDS for weight was derived by comparing the actual measurements with standard growth charts for the United States. Standard values provided by the standard growth charts according to the subject's sex and age at the time of the measurement were used to calculate the SDS.

2. Proportion of Subjects Achieving HbA1c Below 7.0%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment. [At week 26]

   Proportion of subjects achieving HbA1c <7.0% is presented as percentage of subjects achieving HbA1c <7.0%, who have not experienced any treatment emergent severe hypoglycaemic episodes (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) within the last 14 weeks of treatment.

3. Proportion of Subjects Achieving HbA1c Below 7.5%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment [At week 26]

   Proportion of subjects achieving HbA1c below 7.5% is presented as percentage of subjects achieving HbA1c <7.5%, who have not experienced any treatment emergent severe hypoglycaemic episodes (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) within the last 14 weeks of treatment.

4. Total Number of Treatment Emergent Nocturnal (23:00-06:59) Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes [Weeks 0 - 26]

   The total number of blood glucose confirmed symptomatic nocturnal (time of onset between 23:00 and 06.59 both inclusive) severe (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or blood glucose confirmed symptomatic hypoglycaemic episodes (plasma glucose value <3.1 mmol/L [56 mg/dL] with symptoms consistent with hypoglycaemia) experienced by the subjects during the trial.

5. Total Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes [Weeks 0 - 26]

   Total number of treatment emergent severe (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or blood glucose confirmed symptomatic hypoglycaemic episodes (plasma glucose value <3.1 mmol/L [56 mg/dL] with symptoms consistent with hypoglycaemia) experienced by the subjects during the trial.

6. Incidence of Adverse Events (AEs) [weeks 0 - 26]

   The total number of treatment emergent adverse events (the onset of the adverse event is on or after the first day of trial product administration, and no later than 7 days after the last day of trial product administration) reported during the 26 weeks of treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent from the subject or a legally acceptable representative (LAR) and child assent from the subject obtained before any trial-related activities.Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial

• Male or female, above or equal to 10 years and below or equal to 17 years at the time of signing informed consent/assent

• Diagnosis of type 2 diabetes mellitus at least 3 months prior to screening

• Treated with the maximum tolerated stable dose of metformin for at least 3 months prior to screening or have documented complete metformin intolerance

• HbA1c (glycosylated haemoglobin) above or equal to 7.0% and below or equal to 10.5% (above or equal to 53 mmol/mol and below or equal to 91 mmol/mol) at screening

Exclusion Criteria:

• Maturity onset diabetes of the young (MODY)

• Fasting C-peptide at screening below 0.6 ng/mL

• Impaired liver function defined as alanine aminotransferase (ALT) above or equal to 2.5 times upper normal limit

• Known proliferative retinopathy or maculopathy requiring acute treatment as judged by the investigator

• Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 3 months before the day of screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Tucson	Arizona	United States	85724
2	Novo Nordisk Investigational Site	Los Angeles	California	United States	90027
3	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32207
4	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32256
5	Novo Nordisk Investigational Site	Pembroke Pines	Florida	United States	33026
6	Novo Nordisk Investigational Site	Tallahassee	Florida	United States	32308
7	Novo Nordisk Investigational Site	Atlanta	Georgia	United States	30322
8	Novo Nordisk Investigational Site	Silver Spring	Maryland	United States	20910
9	Novo Nordisk Investigational Site	Washington	Maryland	United States	20011
10	Novo Nordisk Investigational Site	Las Vegas	Nevada	United States	89148
11	Novo Nordisk Investigational Site	Buffalo	New York	United States	14203
12	Novo Nordisk Investigational Site	Cleveland	Ohio	United States	44195-0001
13	Novo Nordisk Investigational Site	Toledo	Ohio	United States	43606
14	Novo Nordisk Investigational Site	Hershey	Pennsylvania	United States	17033
15	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19104
16	Novo Nordisk Investigational Site	Pittsburgh	Pennsylvania	United States	15224
17	Novo Nordisk Investigational Site	Providence	Rhode Island	United States	02903
18	Novo Nordisk Investigational Site	Columbia	South Carolina	United States	29203
19	Novo Nordisk Investigational Site	Memphis	Tennessee	United States	38119
20	Novo Nordisk Investigational Site	Amarillo	Texas	United States	79106
21	Novo Nordisk Investigational Site	Edinburg	Texas	United States	78539
22	Novo Nordisk Investigational Site	Norfolk	Virginia	United States	23507
23	Novo Nordisk Investigational Site	Milwaukee	Wisconsin	United States	53226
24	Novo Nordisk Investigational Site	Caba		Argentina	C1425DUC
25	Novo Nordisk Investigational Site	Aparecida de Goiania	Goias	Brazil	74935-530
26	Novo Nordisk Investigational Site	Porto Alegre	Rio Grande Do Sul	Brazil	91350-250
27	Novo Nordisk Investigational Site	São Paulo	Sao Paulo	Brazil	01223-001
28	Novo Nordisk Investigational Site	São Paulo	Sao Paulo	Brazil	01228-000
29	Novo Nordisk Investigational Site	Zagreb		Croatia	10000
30	Novo Nordisk Investigational Site	Alexandria		Egypt	21131
31	Novo Nordisk Investigational Site	Cairo		Egypt	11562
32	Novo Nordisk Investigational Site	Cairo		Egypt	11628
33	Novo Nordisk Investigational Site	Ludwigshafen		Germany	67059
34	Novo Nordisk Investigational Site	Neuwied		Germany	56564
35	Novo Nordisk Investigational Site	Goudi/ Athens		Greece	GR-11527
36	Novo Nordisk Investigational Site	Thessaloniki		Greece	GR 54642
37	Novo Nordisk Investigational Site	Budapest		Hungary	1023
38	Novo Nordisk Investigational Site	Budapest		Hungary	1083
39	Novo Nordisk Investigational Site	Miskolc		Hungary	3501
40	Novo Nordisk Investigational Site	Hyderabad	Andhra Pradesh	India	500072
41	Novo Nordisk Investigational Site	Hyderabad	Andhra Pradesh	India	500082
42	Novo Nordisk Investigational Site	Ahmedabad	Gujarat	India	380007
43	Novo Nordisk Investigational Site	Bangalore	Karnataka	India	560002
44	Novo Nordisk Investigational Site	Bangalore	Karnataka	India	560034
45	Novo Nordisk Investigational Site	Bangalore	Karnataka	India	560045
46	Novo Nordisk Investigational Site	Chennai	Tamil Nadu	India	600 013
47	Novo Nordisk Investigational Site	Kolkata	West Bengal	India	700032
48	Novo Nordisk Investigational Site	Beer Sheva		Israel	84101
49	Novo Nordisk Investigational Site	Haifa		Israel	31096
50	Novo Nordisk Investigational Site	Ancona		Italy	60123
51	Novo Nordisk Investigational Site	Firenze		Italy	50139
52	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	05030
53	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	135-720
54	Novo Nordisk Investigational Site	Beirut		Lebanon
55	Novo Nordisk Investigational Site	Hazmieh		Lebanon	9615
56	Novo Nordisk Investigational Site	Lebanon - Beirut		Lebanon	9611
57	Novo Nordisk Investigational Site	Kota Kinabalu		Malaysia	88996
58	Novo Nordisk Investigational Site	Kuala Lumpur		Malaysia	59100
59	Novo Nordisk Investigational Site	Seremban		Malaysia	70300
60	Novo Nordisk Investigational Site	Seri Manjung		Malaysia	32040
61	Novo Nordisk Investigational Site	Puebla		Mexico	72190
62	Novo Nordisk Investigational Site	Casablanca		Morocco	20000
63	Novo Nordisk Investigational Site	Fès		Morocco	30000
64	Novo Nordisk Investigational Site	Marrakech		Morocco	40000
65	Novo Nordisk Investigational Site	Rabat		Morocco	10000
66	Novo Nordisk Investigational Site	Wroclaw		Poland	50-311
67	Novo Nordisk Investigational Site	Lisboa		Portugal	1250-230
68	Novo Nordisk Investigational Site	Izhevsk		Russian Federation	426009
69	Novo Nordisk Investigational Site	Stavropol		Russian Federation	355017
70	Novo Nordisk Investigational Site	Tomsk		Russian Federation	634034
71	Novo Nordisk Investigational Site	Nis		Serbia	18 000
72	Novo Nordisk Investigational Site	Lenasia	Gauteng	South Africa	1827
73	Novo Nordisk Investigational Site	Pretoria	Gauteng	South Africa	0181
74	Novo Nordisk Investigational Site	Observatory	Western Cape	South Africa	7925
75	Novo Nordisk Investigational Site	Esplugues Llobregat(Barcelona)		Spain	08950
76	Novo Nordisk Investigational Site	Taichung		Taiwan	404
77	Novo Nordisk Investigational Site	Taoyuan		Taiwan	333
78	Novo Nordisk Investigational Site	Adana		Turkey	01130
79	Novo Nordisk Investigational Site	Ankara		Turkey	06100
80	Novo Nordisk Investigational Site	Istanbul		Turkey	34093
81	Novo Nordisk Investigational Site	Istanbul		Turkey	34890
82	Novo Nordisk Investigational Site	Kayseri		Turkey	38010

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: NCT02131272
• Other Study ID Numbers: NN304-4093; 2013-005500-33; U1111-1151-4056; 2015-1316
• First Posted: May 6, 2014
• Last Update Posted: Sep 10, 2018
• Last Verified: Aug 1, 2018

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Insulin Detemir; Isophane Insulin, Human; Insulin, Isophane; Isophane insulin, beef

Study Results

Participant Flow

Recruitment Details	The following 12 countries screened subjects (no. of sites that randomised subjects within parentheses): Brazil (1), Germany (1), India (3), Israel (1), South Korea (1), Malaysia (3), Mexico (1), Russian Federation (1) Taiwan (3), Turkey (3), United States (6), Hungary (0). A total of 24 sites in 11 countries randomised subjects to treatment.
Pre-assignment Detail	Subjects continued treatment with metformin on their pre-study dose(s) throughout the trial.

Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise	Insulin NPH + Metformin + Diet/Exercise
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.
Period Title: Overall Study
STARTED	20	22
COMPLETED	19	20
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise	Insulin NPH + Metformin + Diet/Exercise	Total
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Total of all reporting groups
Overall Participants	20	22	42
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	15.0 (2.1)	15.0 (2.2)	15.0 (2.1)
Sex: Female, Male (Count of Participants)
Female	12 60%	15 68.2%	27 64.3%
Male	8 40%	7 31.8%	15 35.7%
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.72 (0.86)	8.95 (1.05)	8.84 (0.96)
Body weight standard deviation score (standard deviation score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [standard deviation score]	1.532 (0.685)	1.260 (0.835)	1.390 (0.771)

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c (Glycosylated Haemoglobin)
Description	Estimated mean change in HbA1c (glycosylated haemoglobin) from baseline to week 26.
Time Frame	week 0, week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all the randomised subjects.

Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise	Insulin NPH + Metformin + Diet/Exercise
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.
Measure Participants	20	22
Least Squares Mean (Standard Error) [Percentage of glycosylated haemoglobin]	-0.64 (0.32)	-0.81 (0.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Detemir + Metformin + Diet/Exercise, Insulin NPH + Metformin + Diet/Exercise
	Comments	HbA1c measurements were analysed with a mixed model for repeated measurements with an unstructured covariance matrix. The model included treatment, visit, age group, prior antidiabetic therapy and interaction between prior antidiabetic therapy and age group as fixed factors and the HbA1c baseline value as covariate. Interactions between visit and all factors and covariates were also included in the model.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was considered fulfilled if the upper bound of the two-sided 95% confidence interval for the difference between detemir and NPH was below or equal to 0.4%. The sample size was set to ensure 80% power for the full analysis set (FAS). However, efficacy conclusions cannot be drawn from the analysis due to low number of subjects included in the trial.
Statistical Test of Hypothesis	p-Value	0.3075
	Comments	p value is reported for 1 sided test
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; -0.74 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Body Weight Standard Deviation Score (SDS)
Description	Change in body weight standard deviation score (SDS) from baseline to week 26. In order to reduce the variability in body weight measurements, SDS were calculated. SDS for weight was derived by comparing the actual measurements with standard growth charts for the United States. Standard values provided by the standard growth charts according to the subject's sex and age at the time of the measurement were used to calculate the SDS.
Time Frame	week 0, week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all the randomised subjects.

Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise	Insulin NPH + Metformin + Diet/Exercise
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.
Measure Participants	20	22
Mean (Standard Deviation) [standard deviation score]	0.006 (0.192)	0.098 (0.139)

3. Secondary Outcome

Title	Proportion of Subjects Achieving HbA1c Below 7.0%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment.
Description	Proportion of subjects achieving HbA1c <7.0% is presented as percentage of subjects achieving HbA1c <7.0%, who have not experienced any treatment emergent severe hypoglycaemic episodes (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) within the last 14 weeks of treatment.
Time Frame	At week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all the randomised subjects. Only subjects who have been exposed for a minimum of 14 weeks contributed to the analysis (20 subjects in the Insulin detemir + metformin + diet/exercise arm and 21 subjects in the Insulin NPH + metformin + diet/exercise arm).

Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise	Insulin NPH + Metformin + Diet/Exercise
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.
Measure Participants	20	21
Number [Percentage of subjects]	25.0	33.3

4. Secondary Outcome

Title	Proportion of Subjects Achieving HbA1c Below 7.5%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment
Description	Proportion of subjects achieving HbA1c below 7.5% is presented as percentage of subjects achieving HbA1c <7.5%, who have not experienced any treatment emergent severe hypoglycaemic episodes (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) within the last 14 weeks of treatment.
Time Frame	At week 26

Outcome Measure Data

Analysis Population Description

Full analysis set included all the randomised subjects. Only subjects who have been exposed for a minimum of 14 weeks contributed to the analysis (20 subjects in the Insulin detemir + metformin + diet/exercise arm and 21 subjects in the Insulin NPH + metformin + diet/exercise arm).

Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise	Insulin NPH + Metformin + Diet/Exercise
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.
Measure Participants	20	21
Number [Percentage of subjects]	30.0	38.1

5. Secondary Outcome

Title	Total Number of Treatment Emergent Nocturnal (23:00-06:59) Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes
Description	The total number of blood glucose confirmed symptomatic nocturnal (time of onset between 23:00 and 06.59 both inclusive) severe (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or blood glucose confirmed symptomatic hypoglycaemic episodes (plasma glucose value <3.1 mmol/L [56 mg/dL] with symptoms consistent with hypoglycaemia) experienced by the subjects during the trial.
Time Frame	Weeks 0 - 26

Outcome Measure Data

Analysis Population Description

Safety analysis set included all subjects receiving at least one dose of randomised treatment.

Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise	Insulin NPH + Metformin + Diet/Exercise
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.
Measure Participants	20	22
Severe	0	0
Blood glucose confirmed symptomatic	0	1

6. Secondary Outcome

Title	Total Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes
Description	Total number of treatment emergent severe (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or blood glucose confirmed symptomatic hypoglycaemic episodes (plasma glucose value <3.1 mmol/L [56 mg/dL] with symptoms consistent with hypoglycaemia) experienced by the subjects during the trial.
Time Frame	Weeks 0 - 26

Outcome Measure Data

Analysis Population Description

Safety analysis set included all subjects receiving at least one dose of randomised treatment.

Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise	Insulin NPH + Metformin + Diet/Exercise
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.
Measure Participants	20	22
Severe	0	0
Blood glucose confirmed symptomatic	4	12

7. Secondary Outcome

Title	Incidence of Adverse Events (AEs)
Description	The total number of treatment emergent adverse events (the onset of the adverse event is on or after the first day of trial product administration, and no later than 7 days after the last day of trial product administration) reported during the 26 weeks of treatment.
Time Frame	weeks 0 - 26

Outcome Measure Data

Analysis Population Description

Safety analysis set included all subjects receiving at least one dose of randomised treatment.

Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise	Insulin NPH + Metformin + Diet/Exercise
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.	Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.
Measure Participants	20	22
Number [Number of events]	30	41

Adverse Events

Time Frame	Adverse events from the first trial-related activity (week -2) after the subject and/or his/her legally acceptable representative has signed the informed consent until the end of the trial (week 26).
Adverse Event Reporting Description	Safety analysis set included all subjects receiving at least one dose of randomised treatment. A treatment emergent adverse event was defined as an event that had the onset date on or after the first day of trial product administration, and no later than 7 days after the last day of trial product administration.
Arm/Group Title	Insulin Detemir + Metformin + Diet/Exercise		Insulin NPH + Metformin + Diet/Exercise
Arm/Group Description	Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.		Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours.
All Cause Mortality
	Insulin Detemir + Metformin + Diet/Exercise		Insulin NPH + Metformin + Diet/Exercise
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Insulin Detemir + Metformin + Diet/Exercise		Insulin NPH + Metformin + Diet/Exercise
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		1/22 (4.5%)
Nervous system disorders
Migraine	0/20 (0%)	0	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	Insulin Detemir + Metformin + Diet/Exercise		Insulin NPH + Metformin + Diet/Exercise
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/20 (40%)		9/22 (40.9%)
Ear and labyrinth disorders
Vertigo	1/20 (5%)	2	0/22 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/20 (5%)	1	1/22 (4.5%)	1
Lip dry	1/20 (5%)	1	0/22 (0%)	0
Toothache	0/20 (0%)	0	2/22 (9.1%)	2
Vomiting	2/20 (10%)	4	0/22 (0%)	0
General disorders
Injection site erythema	1/20 (5%)	1	0/22 (0%)	0
Pyrexia	2/20 (10%)	2	0/22 (0%)	0
Infections and infestations
Gastroenteritis	2/20 (10%)	2	0/22 (0%)	0
Gastroenteritis viral	1/20 (5%)	1	0/22 (0%)	0
Impetigo	1/20 (5%)	1	0/22 (0%)	0
Influenza	0/20 (0%)	0	2/22 (9.1%)	3
Nasopharyngitis	0/20 (0%)	0	2/22 (9.1%)	2
Upper respiratory tract infection	1/20 (5%)	1	1/22 (4.5%)	2
Viral infection	1/20 (5%)	1	0/22 (0%)	0
Injury, poisoning and procedural complications
Arthropod bite	1/20 (5%)	1	0/22 (0%)	0
Soft tissue injury	1/20 (5%)	1	0/22 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	1/20 (5%)	4	0/22 (0%)	0
Nervous system disorders
Headache	3/20 (15%)	4	1/22 (4.5%)	4
Respiratory, thoracic and mediastinal disorders
Cough	1/20 (5%)	1	0/22 (0%)	0
Oropharyngeal pain	1/20 (5%)	1	3/22 (13.6%)	3
Rhinitis allergic	1/20 (5%)	1	0/22 (0%)	0

Limitations/Caveats

The trial was terminated earlier than planned due to a very slow recruitment rate. Based on the low number of subjects, the conclusions should be interpreted with caution.

More Information

Certain Agreements

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

At the end of the trial, one or more scientific publications 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.