BEGIN™: Comparing the Efficacy and Safety of NN1250 Once Daily When Titrated Using 2 Different Algorithms in Insulin naïve Subjects With Type 2 Diabetes Mellitus

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01326026
• Collaborator: (none)
• Enrollment: 222
• Locations: 45
• Arms: 2
• Duration (Months): 9
• Patients Per Site: 4.9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This trial is conducted in Europe and the United States of America (USA). The aim of this trial is to compare the efficacy and safety of NN1250 (insulin degludec (IDeg)) once daily in insulin naïve subjects with type 2 diabetes mellitus when titrated using two different self-titration algorithms (dose individually adjusted) in combination with metformin.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 222 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Trial Comparing the Efficacy and Safety of Insulin Degludec Once Daily in Insulin naïve Subjects With Type 2 Diabetes Mellitus When Titrated Using Two Different Titration Algorithms (BEGIN™: ONCE SIMPLE USE)
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IDeg Simple	Drug: insulin degludec; Injected subcutaneously (under the skin) once daily. Dose individually adjusted.
Experimental: IDeg Step wise	Drug: insulin degludec; Injected subcutaneously (under the skin) once daily. Dose individually adjusted in a stepwise manner.

Outcome Measures

Primary Outcome Measures

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

   Change from baseline in HbA1c after 26 weeks of treatment.

Secondary Outcome Measures

1. Change in Fasting Plasma Glucose (FPG) [Week 0, Week 26]

   Change from baseline in FPG after 26 weeks of treatment.

2. Rate of Treatment Emergent Adverse Events (AEs) [Week 0 to Week 26 + 7 days follow up]

   Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect.

3. Rate of Confirmed Hypoglycaemic Episodes [Week 0 to Week 26 + 7 days follow up]

   Observed rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L.

4. Rate of Nocturnal Confirmed Hypoglycaemic Episodes [Week 0 to Week 26 + 7 days follow up]

   Observed rate of nocturnal confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occurring between 00:01 and 05:59 a.m.

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 24 weeks prior to randomisation (Visit 2)

• Current treatment: metformin monotherapy or metformin in any combination with 1 or 2 other OADs including an insulin secretagogue (sulfonylurea or glinide), dipeptidyl peptidase IV (DPP-IV) inhibitors, alpha-glucosidase inhibitors, thiazolidinediones (TZDs) all with unchanged dosing for at least 12 weeks prior to randomisation (Visit 2)-metformin: alone or in combination (including fixed combination) must be at least 1000 mg daily

• HbA1c 7.0-10.0% (both inclusive) by central laboratory analysis

• BMI (Body Mass Index) no higher than 45.0 kg/m^2

Exclusion Criteria:

• Treatment with glucagon-like peptide 1 (GLP-1) receptor agonist within the last 12 weeks prior to Visit 2

• Suffer from a life threatening disease (e.g. cancer)

• Females of childbearing potential who are pregnant (as determined by central laboratory beta-human chorionic gonadotropin (beta-hCG), breast feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive methods as required by law or practise [for Germany, adequate contraceptive methods are: implants, injectables, combined oral contraceptives, hormonal IUD, sexual abstinence or vasectomised partner])

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	Huntsville	Alabama	United States	35801
3	Novo Nordisk Investigational Site	Anaheim	California	United States	92801
4	Novo Nordisk Investigational Site	La Jolla	California	United States	92037
5	Novo Nordisk Investigational Site	Mission Hills	California	United States	91345
6	Novo Nordisk Investigational Site	National City	California	United States	91950
7	Novo Nordisk Investigational Site	North Hollywood	California	United States	91606
8	Novo Nordisk Investigational Site	San Diego	California	United States	92111
9	Novo Nordisk Investigational Site	Golden	Colorado	United States	80401
10	Novo Nordisk Investigational Site	Kissimmee	Florida	United States	34741
11	Novo Nordisk Investigational Site	Tampa	Florida	United States	33603
12	Novo Nordisk Investigational Site	Columbus	Georgia	United States	31909
13	Novo Nordisk Investigational Site	Springfield	Illinois	United States	62711
14	Novo Nordisk Investigational Site	Evansville	Indiana	United States	47714
15	Novo Nordisk Investigational Site	Slidell	Louisiana	United States	70461-4231
16	Novo Nordisk Investigational Site	Billings	Montana	United States	59102
17	Novo Nordisk Investigational Site	Staten Island	New York	United States	10301
18	Novo Nordisk Investigational Site	Greensboro	North Carolina	United States	27408
19	Novo Nordisk Investigational Site	Franklin	Ohio	United States	45005
20	Novo Nordisk Investigational Site	Melrose Park	Pennsylvania	United States	19027
21	Novo Nordisk Investigational Site	East Providence	Rhode Island	United States	02914
22	Novo Nordisk Investigational Site	Humboldt	Tennessee	United States	38343
23	Novo Nordisk Investigational Site	Houston	Texas	United States	77095
24	Novo Nordisk Investigational Site	Killeen	Texas	United States	76543-5600
25	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78224
26	Novo Nordisk Investigational Site	Ogden	Utah	United States	84403
27	Novo Nordisk Investigational Site	St. George	Utah	United States	84790
28	Novo Nordisk Investigational Site	Helsinki		Finland	00260
29	Novo Nordisk Investigational Site	Kerava		Finland	FI-04200
30	Novo Nordisk Investigational Site	Tampere		Finland	33210
31	Novo Nordisk Investigational Site	Turku		Finland	20520
32	Novo Nordisk Investigational Site	Turku		Finland	FI-20100
33	Novo Nordisk Investigational Site	Berlin		Germany	12163
34	Novo Nordisk Investigational Site	Friedrichsthal		Germany	66299
35	Novo Nordisk Investigational Site	Hohenmölsen		Germany	06679
36	Novo Nordisk Investigational Site	Münster		Germany	48145
37	Novo Nordisk Investigational Site	Neuwied		Germany	56564
38	Novo Nordisk Investigational Site	Völklingen		Germany	66333
39	Novo Nordisk Investigational Site	Almería		Spain	04001
40	Novo Nordisk Investigational Site	Antequera		Spain	29200
41	Novo Nordisk Investigational Site	Gijón		Spain	33206
42	Novo Nordisk Investigational Site	Málaga		Spain	29006
43	Novo Nordisk Investigational Site	Palma de Mallorca		Spain	07014
44	Novo Nordisk Investigational Site	Palma de Mallorca		Spain	07198
45	Novo Nordisk Investigational Site	Pozuelo de Alarcon		Spain	28223

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: NCT01326026
• Other Study ID Numbers: NN1250-3846; U1111-1117-0616; 2010-022337-29
• First Posted: Mar 30, 2011
• Last Update Posted: Mar 6, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Insulin, Long-Acting

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 43 sites in 4 countries: Finland (5), Germany (6), Spain (6) and United States of America (26).
Pre-assignment Detail	Subjects continued on metformin treatment at the pre-randomisation dose level and dosing frequency.

Arm/Group Title	IDeg Simple	IDeg Step Wise
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to simple titration algorithm: self-titration was performed once weekly based upon a single pre-breakfast self measured plasma glucose (SMPG) value measured on the day of insulin titration.	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to step wise titration algorithm: self-titration was performed once weekly based on the lowest value of three pre-breakfast SMPG values measured on three consecutive days, the two days prior to and on the day of insulin titration.
Period Title: Overall Study
STARTED	111	111
Exposed	110	111
COMPLETED	99	98
NOT COMPLETED	12	13

Baseline Characteristics

Arm/Group Title	IDeg Simple	IDeg Step Wise	Total
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to simple titration algorithm: self-titration was performed once weekly based upon a single pre-breakfast self measured plasma glucose (SMPG) value measured on the day of insulin titration.	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to step wise titration algorithm: self-titration was performed once weekly based on the lowest value of three pre-breakfast SMPG values measured on three consecutive days, the two days prior to and on the day of insulin titration.	Total of all reporting groups
Overall Participants	111	111	222
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.4 (9.5)	58.5 (11.1)	58.9 (10.3)
Sex: Female, Male (Count of Participants)
Female	43 38.7%	36 32.4%	79 35.6%
Male	68 61.3%	75 67.6%	143 64.4%
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.1 (0.9)	8.2 (0.9)	8.1 (0.9)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	9.3 (2.6)	9.4 (2.8)	9.4 (2.7)

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c)
Description	Change from baseline in HbA1c after 26 weeks of treatment.
Time Frame	Week 0, Week 26

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) included all randomised subjects and missing data was imputed using last observation carried forward (LOCF).

Arm/Group Title	IDeg Simple	IDeg Step Wise
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to simple titration algorithm: self-titration was performed once weekly based upon a single pre-breakfast self measured plasma glucose (SMPG) value measured on the day of insulin titration.	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to step wise titration algorithm: self-titration was performed once weekly based on the lowest value of three pre-breakfast SMPG values measured on three consecutive days, the two days prior to and on the day of insulin titration.
Measure Participants	111	111
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	-1.09 (1.05)	-0.93 (0.97)

2. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG)
Description	Change from baseline in FPG after 26 weeks of treatment.
Time Frame	Week 0, Week 26

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) included all randomised subjects and missing data was imputed using last observation carried forward (LOCF). For 7 subjects baseline values were missing.

Arm/Group Title	IDeg Simple	IDeg Step Wise
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to simple titration algorithm: self-titration was performed once weekly based upon a single pre-breakfast self measured plasma glucose (SMPG) value measured on the day of insulin titration.	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to step wise titration algorithm: self-titration was performed once weekly based on the lowest value of three pre-breakfast SMPG values measured on three consecutive days, the two days prior to and on the day of insulin titration.
Measure Participants	108	107
Mean (Standard Deviation) [mmol/L]	-3.27 (3.56)	-2.68 (3.50)

3. Secondary Outcome

Title	Rate of Treatment Emergent Adverse Events (AEs)
Description	Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect.
Time Frame	Week 0 to Week 26 + 7 days follow up

Outcome Measure Data

Analysis Population Description

The safety analysis set included all subjects who received at least one dose of the investigational product.

Arm/Group Title	IDeg Simple	IDeg Step Wise
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to simple titration algorithm: self-titration was performed once weekly based upon a single pre-breakfast self measured plasma glucose (SMPG) value measured on the day of insulin titration.	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to step wise titration algorithm: self-titration was performed once weekly based on the lowest value of three pre-breakfast SMPG values measured on three consecutive days, the two days prior to and on the day of insulin titration.
Measure Participants	110	111
Adverse events (AEs)	346	379
Serious AEs	15	15
Severe AEs	15	10
Moderate AEs	69	79
Mild AEs	262	291
Fatal AEs	0	2

4. Secondary Outcome

Title	Rate of Confirmed Hypoglycaemic Episodes
Description	Observed rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L.
Time Frame	Week 0 to Week 26 + 7 days follow up

Outcome Measure Data

Analysis Population Description

The safety analysis set included all subjects who received at least one dose of the investigational product.

Arm/Group Title	IDeg Simple	IDeg Step Wise
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to simple titration algorithm: self-titration was performed once weekly based upon a single pre-breakfast self measured plasma glucose (SMPG) value measured on the day of insulin titration.	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to step wise titration algorithm: self-titration was performed once weekly based on the lowest value of three pre-breakfast SMPG values measured on three consecutive days, the two days prior to and on the day of insulin titration.
Measure Participants	110	111
Number [Episodes/100 years of patient exposure]	160	117

5. Secondary Outcome

Title	Rate of Nocturnal Confirmed Hypoglycaemic Episodes
Description	Observed rate of nocturnal confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occurring between 00:01 and 05:59 a.m.
Time Frame	Week 0 to Week 26 + 7 days follow up

Outcome Measure Data

Analysis Population Description

The safety analysis set included all subjects who received at least one dose of the investigational product.

Arm/Group Title	IDeg Simple	IDeg Step Wise
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to simple titration algorithm: self-titration was performed once weekly based upon a single pre-breakfast self measured plasma glucose (SMPG) value measured on the day of insulin titration.	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to step wise titration algorithm: self-titration was performed once weekly based on the lowest value of three pre-breakfast SMPG values measured on three consecutive days, the two days prior to and on the day of insulin titration.
Measure Participants	110	111
Number [Episodes/100 years of patient exposure]	21	10

Adverse Events

Time Frame	The adverse events were collected in a time frame of 26 weeks + 7 days follow up
Adverse Event Reporting Description	The safety analysis set included all subjects who received at least one dose of the investigational product.
Arm/Group Title	IDeg Simple		IDeg Step Wise
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to simple titration algorithm: self-titration was performed once weekly based upon a single pre-breakfast self measured plasma glucose (SMPG) value measured on the day of insulin titration.		Insulin degludec (IDeg) was given once daily (OD) subcutaneously (approximately 8-40 hours intervals between doses) with pre-trial metformin according to step wise titration algorithm: self-titration was performed once weekly based on the lowest value of three pre-breakfast SMPG values measured on three consecutive days, the two days prior to and on the day of insulin titration.
All Cause Mortality
	IDeg Simple		IDeg Step Wise
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	IDeg Simple		IDeg Step Wise
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/110 (4.5%)		7/111 (6.3%)
Cardiac disorders
Acute myocardial infarction	2/110 (1.8%)	2	0/111 (0%)	0
Arteriosclerosis coronary artery	0/110 (0%)	0	1/111 (0.9%)	1
Atrioventricular block complete	1/110 (0.9%)	1	0/111 (0%)	0
Coronary artery occlusion	0/110 (0%)	0	1/111 (0.9%)	1
Coronary artery stenosis	1/110 (0.9%)	1	0/111 (0%)	0
Congenital, familial and genetic disorders
Gastrointestinal angiodysplasia	1/110 (0.9%)	1	0/111 (0%)	0
Ear and labyrinth disorders
Vertigo	1/110 (0.9%)	1	0/111 (0%)	0
Gastrointestinal disorders
Retroperitoneal haematoma	1/110 (0.9%)	1	0/111 (0%)	0
Infections and infestations
Bronchitis	0/110 (0%)	0	1/111 (0.9%)	1
Injury, poisoning and procedural complications
Accidental overdose	0/110 (0%)	0	1/111 (0.9%)	1
Contusion	0/110 (0%)	0	1/111 (0.9%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/110 (0%)	0	1/111 (0.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Astrocytoma	1/110 (0.9%)	1	0/111 (0%)	0
Metastases to liver	0/110 (0%)	0	1/111 (0.9%)	1
Psychiatric disorders
Panic attack	0/110 (0%)	0	1/111 (0.9%)	1
Other (Not Including Serious) Adverse Events
	IDeg Simple		IDeg Step Wise
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/110 (15.5%)		14/111 (12.6%)
Infections and infestations
Nasopharyngitis	10/110 (9.1%)	10	7/111 (6.3%)	8
Nervous system disorders
Headache	8/110 (7.3%)	8	8/111 (7.2%)	14

Limitations/Caveats

[Not Specified]

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. Any such communication must be submitted in writing to the Novo Nordisk trial manager prior to submission for comments. Comments will be given within four weeks from receipt of the planned communication.