BEGIN™: Comparison of NN1250 Versus Insulin Glargine in Subjects With Type 2 Diabetes

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01059799
• Collaborator: (none)
• Enrollment: 435
• Locations: 53
• Arms: 2
• Actual Duration (Months): 10.4
• Patients Per Site: 8.2
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This trial is conducted in Asia and Japan. The aim of this trial is to compare insulin degludec (NN1250) with insulin glargine both combined with oral antidiabetic drugs (OADs) in subjects with type 2 diabetes never treated with insulin.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 435 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pan Asian Trial Comparing Efficacy and Safety of Insulin NN1250 and Insulin Glargine as Add on to OAD(s) in Subjects With Type 2 Diabetes (BEGIN™: ONCE ASIA)
• Actual Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Dec 16, 2010
• Actual Study Completion Date: Dec 16, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IDeg OD	Drug: insulin degludec; Insulin degludec injected subcutaneously (under the skin) once daily. The doses will be individually adjusted
Active Comparator: IGlar OD	Drug: insulin glargine; Insulin glargine injected subcutaneously (under the skin) once daily. The doses will be individually adjusted

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

   Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure 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.

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

   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.

3. Mean of 9-point Self Measured Plasma Glucose Profile (SMPG) [Week 26]

   Mean of SMPG after 26 weeks of treatment. Plasma glucose measured: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, before bedtime, at 4 am and before breakfast.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• For Japan only: minimum age is 20 years

• Type 2 diabetes mellitus (diagnosed clinically) for at least 6 months

• Current treatment with monotherapy or combination of an insulin secretagouge (sulfonylurea or glinide) and metformin, with or without addition of alfa-glucosidase-inhibitors or a DPP-4 inhibitor with unchanged dosing for at least 3 months prior to visit 1. The dose(s) should as minimum be as stated: -Insulin secretagogue (sulfonylurea or glinide): Minimum half of the daily maximal dose according to local labelling -Metformin: alone or in combination (including fixed combination): Maximum tolerated dose - alfa-glucosidase-inhibitors: Minimum half of the daily maximal dose or maximum tolerated dose -DPP-4 (dipeptyl peptidase 4) inhibitor: According to local labelling

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

• Body Mass Index (BMI) no higher than 35.0 kg/m^2

Exclusion Criteria:

• Use within the last 3 months prior to Visit 1 of: TZDs (thiazolidinediones), exenatide or liraglutide

• Cardiovascular disease, within the last 6 months prior to 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 at least 180 millimetre (mm) mercury (Hg) and/or diastolic blood pressure at least 100 mmHg)

• Pregnancy, breast-feeding, or the intention of becoming pregnant or not using adequate contraceptive measures according to local requirements (for Thailand: adequate contraceptive measures are: diaphragm, condom (by the partner), intrauterine device in place for last three months before trial starts, sponge, cap with spermicide, contraceptive patch, approved hormonal implant (i.e. Norplant), oral contraceptives taken without difficulty for the last three months before trial starts, post menopausal state or sterilisation.)

• Cancer and medical history of cancer (except basal cell skin cancer or squamous cell skin cancer)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Shatin, New Territories		Hong Kong
2	Novo Nordisk Investigational Site	Chuo-ku, Tokyo		Japan	103 0002
3	Novo Nordisk Investigational Site	Kamakura-shi, Kanagawa		Japan	247 0072
4	Novo Nordisk Investigational Site	Kawasaki-shi		Japan	212 0024
5	Novo Nordisk Investigational Site	Miyazaki-shi		Japan	880 0034
6	Novo Nordisk Investigational Site	Naka-shi, Ibaraki		Japan	311 0113
7	Novo Nordisk Investigational Site	Nishinomiya-shi, Hygo		Japan	662 0971
8	Novo Nordisk Investigational Site	Ogawa-machi		Japan	355 0321
9	Novo Nordisk Investigational Site	Oita-shi		Japan	870 0039
10	Novo Nordisk Investigational Site	Ota-ku, Tokyo		Japan	144 0035
11	Novo Nordisk Investigational Site	Oyama-shi, Tochigi		Japan	323 0022
12	Novo Nordisk Investigational Site	Sapporo-shi, Hokkaido		Japan	060-0001
13	Novo Nordisk Investigational Site	Takatsuki-shi, Osaka		Japan	569 1096
14	Novo Nordisk Investigational Site	Bucheon		Korea, Republic of	14647
15	Novo Nordisk Investigational Site	Busan		Korea, Republic of	614-735
16	Novo Nordisk Investigational Site	Goyang		Korea, Republic of	10380
17	Novo Nordisk Investigational Site	Goyang		Korea, Republic of	410-719
18	Novo Nordisk Investigational Site	Incheon		Korea, Republic of	400-103
19	Novo Nordisk Investigational Site	Jeonju		Korea, Republic of	561-712
20	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	110-746
21	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	120-752
22	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	130-701
23	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	133-792
24	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	135-239
25	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	135-720
26	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	139-827
27	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	150-950
28	Novo Nordisk Investigational Site	Seoul		Korea, Republic of	158-710
29	Novo Nordisk Investigational Site	Suwon		Korea, Republic of	16247
30	Novo Nordisk Investigational Site	Suwon		Korea, Republic of	16499
31	Novo Nordisk Investigational Site	Wonju		Korea, Republic of	220-701
32	Novo Nordisk Investigational Site	Yangsan		Korea, Republic of	626-770
33	Novo Nordisk Investigational Site	Cheras		Malaysia	56000
34	Novo Nordisk Investigational Site	Georgetown, Penang		Malaysia	10450
35	Novo Nordisk Investigational Site	Kota Bharu, Kelantan		Malaysia	16150
36	Novo Nordisk Investigational Site	Kuala Lumpur		Malaysia	50586
37	Novo Nordisk Investigational Site	Kuala Lumpur		Malaysia	59100
38	Novo Nordisk Investigational Site	Penang		Malaysia	10459
39	Novo Nordisk Investigational Site	Putrajaya		Malaysia	62250
40	Novo Nordisk Investigational Site	Selangor		Malaysia	46150
41	Novo Nordisk Investigational Site	Changhua		Taiwan	500
42	Novo Nordisk Investigational Site	Chiayi City		Taiwan	600
43	Novo Nordisk Investigational Site	Kaohsiung		Taiwan	813
44	Novo Nordisk Investigational Site	Kaoshiung		Taiwan	807
45	Novo Nordisk Investigational Site	Pan-Chiao		Taiwan	220
46	Novo Nordisk Investigational Site	Taichung		Taiwan
47	Novo Nordisk Investigational Site	Taipei		Taiwan	104
48	Novo Nordisk Investigational Site	Bangkoknoi, Bangkok		Thailand	10700
49	Novo Nordisk Investigational Site	Bangkok		Thailand	10330
50	Novo Nordisk Investigational Site	Bangkok		Thailand	10400
51	Novo Nordisk Investigational Site	Chiang Mai		Thailand	50200
52	Novo Nordisk Investigational Site	Nakhon Ratchasima		Thailand	30000
53	Novo Nordisk Investigational Site	Songkla		Thailand	90110

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

• Einhorn D, Handelsman Y, Bode BW, Endahl LA, Mersebach H, King AB. PATIENTS ACHIEVING GOOD GLYCEMIC CONTROL (HBA1c <7%) EXPERIENCE A LOWER RATE OF HYPOGLYCEMIA WITH INSULIN DEGLUDEC THAN WITH INSULIN GLARGINE: A META-ANALYSIS OF PHASE 3A TRIALS. Endocr Pract. 2015 Aug;21(8):917-26. doi: 10.4158/EP14523.OR. Epub 2015 Jun 29.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01059799
• Other Study ID Numbers: NN1250-3586; U1111-1113-2441; JapicCTI-101039
• First Posted: Feb 1, 2010
• Last Update Posted: Mar 30, 2017
• Last Verified: Feb 1, 2017

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 52 sites in 6 countries: Hong Kong (1), Japan (12), Malaysia (8), South Korea (19), Thailand (6) and Taiwan (6)
Pre-assignment Detail	Subjects continued on their current treatment with oral antidiabetic drug(s) (OAD(s) treatment except for dipeptyl peptidase-4 (DPP-4) inhibitors, at the pre-randomisation dose level and dosing frequency.

Arm/Group Title	IDeg OD	IGlar OD
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (under the skin) in the evening in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.	Insulin glargine (IGlar) was given once daily (OD) subcutaneously (under the skin) according to approved labelling in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.
Period Title: Overall Study
STARTED	289	146
Exposed	284	146
COMPLETED	258	136
NOT COMPLETED	31	10

Baseline Characteristics

Arm/Group Title	IDeg OD	IGlar OD	Total
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (under the skin) in the evening in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.	Insulin glargine (IGlar) was given once daily (OD) subcutaneously (under the skin) according to approved labelling in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.	Total of all reporting groups
Overall Participants	289	146	435
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.8 (9.8)	58.1 (10.1)	58.6 (9.9)
Sex: Female, Male (Count of Participants)
Female	131 45.3%	71 48.6%	202 46.4%
Male	158 54.7%	75 51.4%	233 53.6%
Glycosylated haemoglobin (HbA1c) (percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	8.4 (0.8)	8.5 (0.8)	8.5 (0.8)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	8.4 (2.1)	8.6 (1.9)	8.5 (2.0)

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 is imputed using last observation carried forward (LOCF).

Arm/Group Title	IDeg OD	IGlar OD
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (under the skin) in the evening in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.	Insulin glargine (IGlar) was given once daily (OD) subcutaneously (under the skin) according to approved labelling in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.
Measure Participants	289	146
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	-1.24 (0.87)	-1.35 (0.87)

2. Secondary Outcome

Title	Rate of Confirmed Hypoglycaemic Episodes
Description	Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure 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 (SAS) included all subjects who received at least one dose of the investigational product or its comparator.

Arm/Group Title	IDeg OD	IGlar OD
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (under the skin) in the evening in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.	Insulin glargine (IGlar) was given once daily (OD) subcutaneously (under the skin) according to approved labelling in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.
Measure Participants	284	146
Number [Episodes/100 years of patient exposure]	298	370

3. Secondary Outcome

Title	Rate of Nocturnal Confirmed Hypoglycaemic Episodes
Description	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 or its comparator.

Arm/Group Title	IDeg OD	IGlar OD
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (under the skin) in the evening in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.	Insulin glargine (IGlar) was given once daily (OD) subcutaneously (under the skin) according to approved labelling in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.
Measure Participants	284	146
Number [Episodes/100 years of patient exposure]	78	124

4. Secondary Outcome

Title	Mean of 9-point Self Measured Plasma Glucose Profile (SMPG)
Description	Mean of SMPG after 26 weeks of treatment. Plasma glucose measured: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, before bedtime, at 4 am and before breakfast.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

The FAS included all randomised subjects.The missing data is imputed using last observation carried forward (LOCF). For 25 subjects all 9-point SMPG values were missing.

Arm/Group Title	IDeg OD	IGlar OD
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (under the skin) in the evening in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.	Insulin glargine (IGlar) was given once daily (OD) subcutaneously (under the skin) according to approved labelling in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.
Measure Participants	270	140
Mean (Standard Deviation) [mmol/L]	8.2 (1.8)	8.0 (1.9)

Adverse Events

Time Frame	The adverse events were collected in a time frame of 26 weeks + 7 days follow up
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	IDeg OD		IGlar OD
Arm/Group Description	Insulin degludec (IDeg) was given once daily (OD) subcutaneously (under the skin) in the evening in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.		Insulin glargine (IGlar) was given once daily (OD) subcutaneously (under the skin) according to approved labelling in combination with pre-trial OADs (except DPP-4 inhibitors) for 26 weeks. Insulin doses were individually adjusted.
All Cause Mortality
	IDeg OD		IGlar OD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	IDeg OD		IGlar OD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/284 (2.8%)		8/146 (5.5%)
Cardiac disorders
Angina unstable	1/284 (0.4%)	1	0/146 (0%)	0
Cardiac failure congestive	0/284 (0%)	0	1/146 (0.7%)	1
Coronary artery disease	0/284 (0%)	0	1/146 (0.7%)	1
Coronary artery occlusion	1/284 (0.4%)	1	0/146 (0%)	0
Gastrointestinal disorders
Colonic polyp	0/284 (0%)	0	1/146 (0.7%)	1
General disorders
Drowning	1/284 (0.4%)	1	0/146 (0%)	0
Infections and infestations
Diverticulitis	1/284 (0.4%)	1	0/146 (0%)	0
Injury, poisoning and procedural complications
Cataract operation complication	1/284 (0.4%)	1	0/146 (0%)	0
Muscle strain	0/284 (0%)	0	1/146 (0.7%)	1
Rib fracture	1/284 (0.4%)	1	0/146 (0%)	0
Road traffic accident	0/284 (0%)	0	1/146 (0.7%)	1
Metabolism and nutrition disorders
Hypoglycaemia	0/284 (0%)	0	1/146 (0.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/284 (0%)	0	1/146 (0.7%)	1
Endometrial cancer	0/284 (0%)	0	1/146 (0.7%)	1
Large intestine carcinoma	1/284 (0.4%)	1	0/146 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/284 (0.4%)	1	0/146 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumothorax	1/284 (0.4%)	1	0/146 (0%)	0
Surgical and medical procedures
Ureteric calculus removal	1/284 (0.4%)	1	0/146 (0%)	0
Other (Not Including Serious) Adverse Events
	IDeg OD		IGlar OD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/284 (20.4%)		39/146 (26.7%)
Eye disorders
Diabetic retinopathy	15/284 (5.3%)	16	6/146 (4.1%)	6
Infections and infestations
Nasopharyngitis	26/284 (9.2%)	32	20/146 (13.7%)	26
Upper respiratory tract infection	22/284 (7.7%)	29	16/146 (11%)	21

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.