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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™)

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ClinicalTrials.gov Identifier: NCT02100475
Recruitment Status : Completed
First Posted : April 1, 2014
Results First Posted : January 20, 2017
Last Update Posted : January 20, 2017
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Diabetes
Diabetes Mellitus, Type 2
Interventions Drug: insulin degludec/liraglutide
Drug: insulin aspart
Enrollment 31
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 Details 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
Hide 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
Reason Not Completed
Unclassified             1             2
Withdrawal criteria             1             0
Arm/Group Title IDegLira IDegLira + IAsp Total
Hide 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 Number of Baseline Participants 16 15 31
Hide Baseline Analysis Population Description
Baseline characteristics were presented for full analysis set (FAS = 31 subjects).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 16 participants 15 participants 31 participants
57.3  (11.7) 57.4  (11.2) 57.4  (11.3)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 15 participants 31 participants
Female
9
  56.3%
8
  53.3%
17
  54.8%
Male
7
  43.8%
7
  46.7%
14
  45.2%
HbA1c  
Mean (Standard Deviation)
Unit of measure:  Percentage of glycosylated haemoglobin
Number Analyzed 16 participants 15 participants 31 participants
7.6  (0.9) 7.7  (0.7) 7.6  (0.8)
1.Primary Outcome
Title Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Hide Description Change from baseline in HbA1c after 26 weeks of treatment.
Time Frame Week 0, week 26
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 16 15
Mean (Standard Deviation)
Unit of Measure: Percentage of glycosylated haemoglobin
-0.43  (0.94) -0.14  (1.09)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.427
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-1.05 to 0.46
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in Body Weight
Hide Description Change from baseline in body weight after 26 weeks of treatment.
Time Frame Week 0, week 26
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all randomised subject (31 subjects). Missing data were imputed using the LOCF method.
Arm/Group Title IDegLira IDegLira + IAsp
Hide 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).
Overall Number of Participants Analyzed 16 15
Mean (Standard Deviation)
Unit of Measure: Kilograms
0.9  (2.1) 1.5  (3.2)
3.Secondary Outcome
Title Number of Treatment-emergent Confirmed Hypoglycaemic Episodes
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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).
Overall Number of Participants Analyzed 16 15
Measure Type: Number
Unit of Measure: Number of episodes
34 4
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
Hide 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 (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
IDegLira IDegLira + IAsp
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/16 (6.25%)      2/15 (13.33%)    
Cardiac disorders     
Acute coronary syndrome  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Chronic myeloid leukaemia  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Renal and urinary disorders     
Renal failure  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Surgical and medical procedures     
Coronary revascularisation  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
IDegLira IDegLira + IAsp
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   11/16 (68.75%)      3/15 (20.00%)    
Blood and lymphatic system disorders     
Anaemia  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Eye disorders     
Macular degeneration  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Diarrhoea  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Tooth disorder  1  1/16 (6.25%)  2 0/15 (0.00%)  0
General disorders     
Oedema peripheral  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Infections and infestations     
Bronchitis  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Upper respiratory tract infection  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Urinary tract infection  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Investigations     
Amylase increased  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Blood calcitonin increased  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Cardiac murmur  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Lipase increased  1  1/16 (6.25%)  1 1/15 (6.67%)  1
Metabolism and nutrition disorders     
Dyslipidaemia  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Hyperkalaemia  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Musculoskeletal and connective tissue disorders     
Back pain  1  1/16 (6.25%)  1 1/15 (6.67%)  1
Pain in extremity  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Tendonitis  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Nervous system disorders     
Headache  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Neuropathy peripheral  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Sciatica  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Psychiatric disorders     
Insomnia  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Renal and urinary disorders     
Renal cyst  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Respiratory, thoracic and mediastinal disorders     
Asthma  1  0/16 (0.00%)  0 1/15 (6.67%)  1
Skin and subcutaneous tissue disorders     
Seborrhoeic dermatitis  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Vascular disorders     
Hypertension  1  1/16 (6.25%)  1 0/15 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Due to the small number of subjects in this trial, the data should be interpreted with caution.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Public Access to Clinical Trials
Organization: Novo Nordisk A/S
EMail: clinicaltrials@novonordisk.com
Layout table for additonal information
Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT02100475     History of Changes
Other Study ID Numbers: NN9068-4119
2013-002878-47 ( EudraCT Number )
U1111-1145-0183 ( Other Identifier: WHO )
First Submitted: March 27, 2014
First Posted: April 1, 2014
Results First Submitted: November 23, 2016
Results First Posted: January 20, 2017
Last Update Posted: January 20, 2017