DUAL™: A Trial Comparing Sequential Addition of Insulin Aspart Versus Further Dose Increase With Insulin Degludec/Liraglutide in Subjects With Type 2 Diabetes Mellitus, Previously Treated With Insulin Degludec/Liraglutide and Metformin and in Need of Further Intensification

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02100475
• Collaborator: (none)
• Enrollment: 31
• Locations: 60
• Arms: 2
• Duration (Months): 12
• 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 compare sequential addition of insulin aspart versus further dose increase with insulin degludec/liraglutide in subjects with type 2 diabetes mellitus, previously treated with insulin degludec/liraglutide and metformin and in need of further intensification.

This is an extension to trial NN9068-3952, NCT01952145 (DUAL™ V).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Trial Comparing Sequential Addition of Insulin Aspart Versus Further Dose Increase With Insulin Degludec/Liraglutide in Subjects With Type 2 Diabetes Mellitus, Previously Treated With Insulin Degludec/Liraglutide and Metformin and in Need of Further Intensification (DUAL™ - Intensification)
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Insulin degludec/liraglutide + Metformin	Drug: insulin degludec/liraglutide; Insulin degludec/liraglutide will be given subcutaneously (s.c., under the skin) once daily in combination with metformin. Dose individually adjusted.
Active Comparator: Insulin degludec/liraglutide + Insulin Aspart + Metformin	Drug: insulin degludec/liraglutide; Insulin degludec/liraglutide will be given subcutaneously (s.c., under the skin) once daily in combination with metformin. Dose individually adjusted.; Drug: insulin aspart; Dose titration of insulin aspart will be based on the respective pre-meal(s) and bedtime SMPG measured daily.

Outcome Measures

Primary Outcome Measures

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

   Change from baseline in HbA1c after 26 weeks of treatment.

Secondary Outcome Measures

1. Change From Baseline in Body Weight [Week 0, week 26]

   Change from baseline in body weight after 26 weeks of treatment.

2. Number of Treatment-emergent Confirmed Hypoglycaemic Episodes [Week 0 - 26]

   Treatment-emergent hypoglycaemic episodes: if the onset of the episode occurred on or after the first day of investigational medicinal product administration, and no later than 7 days after the last day on investigational medicinal product. Confirmed hypoglycaemia: subject unable to treat himself/herself and/or have a recorded plasma glucose < 3.1 mmol/L (56 mg/dL).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Completion (Visit 28) of NN9068-3952 with insulin degludec/liraglutide + metformin

• HbA1c (glycosylated haemoglobin) above or equal to 7 percent at Visit 27 of NN9068-3952 trial

Exclusion Criteria:

• Clinically significant diseases of the major organ systems

• Screening calcitonin above or equal to 50 ng/L

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Fresno	California	United States	93720
2	Novo Nordisk Investigational Site	Fort Lauderdale	Florida	United States	33316-2521
3	Novo Nordisk Investigational Site	Gurnee	Illinois	United States	60031
4	Novo Nordisk Investigational Site	Lexington	Kentucky	United States	40503
5	Novo Nordisk Investigational Site	Slidell	Louisiana	United States	70461-4231
6	Novo Nordisk Investigational Site	Altoona	Pennsylvania	United States	16602
7	Novo Nordisk Investigational Site	Renton	Washington	United States	98057
8	Novo Nordisk Investigational Site	Buenos Aires		Argentina	B1704ETD
9	Novo Nordisk Investigational Site	Capital Federal		Argentina	C1056ABJ
10	Novo Nordisk Investigational Site	Corrientes		Argentina	3400
11	Novo Nordisk Investigational Site	Salta		Argentina	4400
12	Novo Nordisk Investigational Site	Zarate		Argentina	B2800DGH
13	Novo Nordisk Investigational Site	Wollongong	New South Wales	Australia	2500
14	Novo Nordisk Investigational Site	Herston	Queensland	Australia	4029
15	Novo Nordisk Investigational Site	Ipswich	Queensland	Australia	4305
16	Novo Nordisk Investigational Site	Robina	Queensland	Australia	4226
17	Novo Nordisk Investigational Site	East Ringwood	Victoria	Australia	3135
18	Novo Nordisk Investigational Site	Athens		Greece	GR-11527
19	Novo Nordisk Investigational Site	Ioannina		Greece	45500
20	Novo Nordisk Investigational Site	Larissa		Greece	GR-41110
21	Novo Nordisk Investigational Site	Thessaloniki		Greece	GR-54642
22	Novo Nordisk Investigational Site	Thessaloniki		Greece	GR-57001
23	Novo Nordisk Investigational Site	Eger		Hungary	3300
24	Novo Nordisk Investigational Site	Gyor		Hungary	9024
25	Novo Nordisk Investigational Site	Gyula		Hungary	5700
26	Novo Nordisk Investigational Site	Miskolc		Hungary	3526
27	Novo Nordisk Investigational Site	Pachuca	Hidalgo	Mexico	42084
28	Novo Nordisk Investigational Site	Cuernavaca	Morelos	Mexico	62250
29	Novo Nordisk Investigational Site	Mexico City	México, D.F.	Mexico	03300
30	Novo Nordisk Investigational Site	Monterrey		Mexico	64460
31	Novo Nordisk Investigational Site	Kazan		Russian Federation	420073
32	Novo Nordisk Investigational Site	Kirov		Russian Federation	610014
33	Novo Nordisk Investigational Site	Moscow		Russian Federation	117036
34	Novo Nordisk Investigational Site	Moscow		Russian Federation	123448
35	Novo Nordisk Investigational Site	Novosibirsk		Russian Federation	630117
36	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	194358
37	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	199034
38	Novo Nordisk Investigational Site	St. Petersburg		Russian Federation	194354
39	Novo Nordisk Investigational Site	Tomsk		Russian Federation	634034
40	Novo Nordisk Investigational Site	Tomsk		Russian Federation	634041
41	Novo Nordisk Investigational Site	Volgograd		Russian Federation	400131
42	Novo Nordisk Investigational Site	Bardejov		Slovakia	08501
43	Novo Nordisk Investigational Site	Dolny Kubin		Slovakia	02601
44	Novo Nordisk Investigational Site	Kosice		Slovakia	040 11
45	Novo Nordisk Investigational Site	Levice		Slovakia	93401
46	Novo Nordisk Investigational Site	Poprad		Slovakia	05801
47	Novo Nordisk Investigational Site	Povazska Bystrica		Slovakia	01701
48	Novo Nordisk Investigational Site	Prievidza		Slovakia	97101
49	Novo Nordisk Investigational Site	Trnava		Slovakia	91701
50	Novo Nordisk Investigational Site	Velky Meder		Slovakia	93201
51	Novo Nordisk Investigational Site	Midrand	Gauteng	South Africa	1685
52	Novo Nordisk Investigational Site	Durban	KwaZulu-Natal	South Africa	4450
53	Novo Nordisk Investigational Site	Brits	North West	South Africa	0250
54	Novo Nordisk Investigational Site	Alberton		South Africa	1449
55	Novo Nordisk Investigational Site	Almería		Spain	04001
56	Novo Nordisk Investigational Site	Granada		Spain	18012
57	Novo Nordisk Investigational Site	Palma de Mallorca		Spain	07014
58	Novo Nordisk Investigational Site	Sevilla		Spain	41003
59	Novo Nordisk Investigational Site	Sevilla		Spain	41010
60	Novo Nordisk Investigational Site	Valencia		Spain	46026

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: NCT02100475
• Other Study ID Numbers: NN9068-4119; 2013-002878-47; U1111-1145-0183
• First Posted: Apr 1, 2014
• Last Update Posted: Jan 20, 2017
• Last Verified: Nov 1, 2016

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 19 sites in 8 countries as follows: Argentina: 2 sites; Greece: 2 sites, Hungary: 1 site; Russian Federation: 5 sites; Slovakia: 4 sites, South Africa: 1 site; Spain: 1 site, United States: 3 sites.
Pre-assignment Detail	Subjects with type 2 diabetes mellitus who were inadequately controlled (HbA1c level ≥ 7% [53 mmol/mol]) on treatment with IDegLira and metformin after 26 weeks of treatment in the NN9068-3952 trial were screened. Eligible subjects were randomised in a 1:1 manner to one of the two parallel treatment groups (IDegLira or IDegLira + IAsp).

Arm/Group Title	IDegLira	IDegLira + IAsp
Arm/Group Description	Insulin degludec/liraglutide (IDegLira) was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. Intensification with IDegLira was performed by dose optimisation up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).	IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. IDegLira was titrated up to a maximum dose of 50 dose steps (50 units IDeg/1.8 mg Lira) with sequential add-on of bolus insulin aspart (IAsp). Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).
Period Title: Overall Study
STARTED	16	15
COMPLETED	14	13
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	IDegLira	IDegLira + IAsp	Total
Arm/Group Description	Insulin degludec/liraglutide (IDegLira) was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. Intensification with IDegLira was performed by dose optimisation up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).	IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. IDegLira was titrated up to a maximum dose of 50 dose steps (50 units IDeg/1.8 mg Lira) with sequential add-on of bolus insulin aspart (IAsp). Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).	Total of all reporting groups
Overall Participants	16	15	31
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	57.3 (11.7)	57.4 (11.2)	57.4 (11.3)
Gender (Count of Participants)
Female	9 56.3%	8 53.3%	17 54.8%
Male	7 43.8%	7 46.7%	14 45.2%
HbA1c (Percentage of glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of glycosylated haemoglobin]	7.6 (0.9)	7.7 (0.7)	7.6 (0.8)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomised subjects (31 subjects). Missing data were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	IDegLira	IDegLira + IAsp
Arm/Group Description	Insulin degludec/liraglutide (IDegLira) was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. Intensification with IDegLira was performed by dose optimisation up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).	IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. IDegLira was titrated up to a maximum dose of 50 dose steps (50 units IDeg/1.8 mg Lira) with sequential add-on of bolus insulin aspart (IAsp). Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).
Measure Participants	16	15
Mean (Standard Deviation) [Percentage of glycosylated haemoglobin]	-0.43 (0.94)	-0.14 (1.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IDegLira, IDegLira + IAsp
	Comments	The response and change from baseline in the response after 26 weeks of treatment was analysed using an analysis of covariance (ANCOVA) method with treatment and baseline IDegLira dose strata as fixed factors and baseline response as a covariate. Missing data were imputed using LOCF.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.427
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -1.05 to 0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Change from baseline in body weight after 26 weeks of treatment.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

FAS included all randomised subject (31 subjects). Missing data were imputed using the LOCF method.

Arm/Group Title	IDegLira	IDegLira + IAsp
Arm/Group Description	Insulin degludec/liraglutide (IDegLira) was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. Intensification with IDegLira was performed by dose optimisation up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).	IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. IDegLira was titrated up to a maximum dose of 50 dose steps (50 units IDeg/1.8 mg Lira) with sequential add-on of bolus insulin aspart (IAsp). Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).
Measure Participants	16	15
Mean (Standard Deviation) [Kilograms]	0.9 (2.1)	1.5 (3.2)

3. Secondary Outcome

Title	Number of Treatment-emergent Confirmed Hypoglycaemic Episodes
Description	Treatment-emergent hypoglycaemic episodes: if the onset of the episode occurred on or after the first day of investigational medicinal product administration, and no later than 7 days after the last day on investigational medicinal product. Confirmed hypoglycaemia: subject unable to treat himself/herself and/or have a recorded plasma glucose < 3.1 mmol/L (56 mg/dL).
Time Frame	Week 0 - 26

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (31 subjects). Confirmed hypoglycaemic episodes were reported by 2 subjects in IDegLira arm and 2 subjects in IDegLira + IAsp arm.

Arm/Group Title	IDegLira	IDegLira + IAsp
Arm/Group Description	Insulin degludec/liraglutide (IDegLira) was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. Intensification with IDegLira was performed by dose optimisation up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).	IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. IDegLira was titrated up to a maximum dose of 50 dose steps (50 units IDeg/1.8 mg Lira) with sequential add-on of bolus insulin aspart (IAsp). Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).
Measure Participants	16	15
Number [Number of episodes]	34	4

Adverse Events

Time Frame	From first trial-related activity (week 0) after the subject had signed the informed consent until the end of the post-treatment follow-up period (week 27).
Adverse Event Reporting Description	SAS included all subjects receiving at least one dose of the investigational product or comparator, (SAS = 31 subjects). A treatment-emergent adverse event (TEAE) was defined as an event that had an onset date on or after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment.
Arm/Group Title	IDegLira		IDegLira + IAsp
Arm/Group Description	Insulin degludec/liraglutide (IDegLira) was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. Intensification with IDegLira was performed by dose optimisation up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).		IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. The starting dose of IDegLira was the dose of IDegLira used at the end of the NN9068-3952 trial. IDegLira was titrated up to a maximum dose of 50 dose steps (50 units IDeg/1.8 mg Lira) with sequential add-on of bolus insulin aspart (IAsp). Dose titration of insulin aspart was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).
All Cause Mortality
	IDegLira		IDegLira + IAsp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	IDegLira		IDegLira + IAsp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/16 (6.3%)		2/15 (13.3%)
Cardiac disorders
Acute coronary syndrome	1/16 (6.3%)	1	0/15 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chronic myeloid leukaemia	0/16 (0%)	0	1/15 (6.7%)	1
Renal and urinary disorders
Renal failure	0/16 (0%)	0	1/15 (6.7%)	1
Surgical and medical procedures
Coronary revascularisation	1/16 (6.3%)	1	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	IDegLira		IDegLira + IAsp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/16 (68.8%)		3/15 (20%)
Blood and lymphatic system disorders
Anaemia	1/16 (6.3%)	1	0/15 (0%)	0
Eye disorders
Macular degeneration	1/16 (6.3%)	1	0/15 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/16 (0%)	0	1/15 (6.7%)	1
Diarrhoea	0/16 (0%)	0	1/15 (6.7%)	1
Tooth disorder	1/16 (6.3%)	2	0/15 (0%)	0
General disorders
Oedema peripheral	0/16 (0%)	0	1/15 (6.7%)	1
Infections and infestations
Bronchitis	1/16 (6.3%)	1	0/15 (0%)	0
Upper respiratory tract infection	0/16 (0%)	0	1/15 (6.7%)	1
Urinary tract infection	1/16 (6.3%)	1	0/15 (0%)	0
Investigations
Amylase increased	0/16 (0%)	0	1/15 (6.7%)	1
Blood calcitonin increased	1/16 (6.3%)	1	0/15 (0%)	0
Cardiac murmur	0/16 (0%)	0	1/15 (6.7%)	1
Lipase increased	1/16 (6.3%)	1	1/15 (6.7%)	1
Metabolism and nutrition disorders
Dyslipidaemia	1/16 (6.3%)	1	0/15 (0%)	0
Hyperkalaemia	0/16 (0%)	0	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/16 (6.3%)	1	1/15 (6.7%)	1
Pain in extremity	1/16 (6.3%)	1	0/15 (0%)	0
Tendonitis	1/16 (6.3%)	1	0/15 (0%)	0
Nervous system disorders
Headache	1/16 (6.3%)	1	0/15 (0%)	0
Neuropathy peripheral	1/16 (6.3%)	1	0/15 (0%)	0
Sciatica	1/16 (6.3%)	1	0/15 (0%)	0
Psychiatric disorders
Insomnia	1/16 (6.3%)	1	0/15 (0%)	0
Renal and urinary disorders
Renal cyst	0/16 (0%)	0	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	0/16 (0%)	0	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Seborrhoeic dermatitis	1/16 (6.3%)	1	0/15 (0%)	0
Vascular disorders
Hypertension	1/16 (6.3%)	1	0/15 (0%)	0

Limitations/Caveats

Due to the small number of subjects in this trial, the data should be interpreted with caution.

More Information

Certain Agreements

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

At the end of trial, one or more scientific publications may be prepared collaboratively by the investigators and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.